Biheteroaryl compounds and uses thereof

ABSTRACT

The present invention provides for compounds of Formula I and embodiments and salts thereof for the treatment of diseases (e.g., neurodegenerative diseases). R 1 , R 2 , R 3 , X 1 , X 2 , A and Cy variable in Formula all have the meaning as defined herein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.15/852,235, filed Dec. 22, 2017, which is a continuation of U.S.application Ser. No. 15/041,375, filed Feb. 11, 2016, now U.S. Pat. No.10,028,954, which is a divisional of U.S. application Ser. No.14/267,011, filed May 1, 2014, now U.S. Pat. No. 9,266,862, which claimsthe benefit of U.S. Provisional Appl. No. 61/817,966, filed on May 1,2013, each of which are incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a mammal, and in particular to inhibitors of DLKuseful for treating neurodegeneration diseases and disorders.

BACKGROUND OF THE INVENTION

Neuron or axon degeneration plays a central role in the properdevelopment of the nervous system and is a hall mark of manyneurodegenerative diseases including for example, amyotrophic lateralsclerosis (ALS), glaucoma, Alzheimer's disease, and Parkinson's disease,as well a traumatic injury to the brain and spinal cord. Recent patentpublication WO2011/050192, incorporated herein by reference, describesthe role of the Dual Leucine Zipper Kinase (DLK), also referred to asMAP3K12, to cause neuronal cell death. Neurodegenerative diseases andinjuries are devastating to patients and caregivers, and also result ingreat financial burdens, with annual costs currently exceeding severalhundred billion dollars in the United States alone. Most currenttreatments for these diseases and conditions are inadequate. Adding tothe urgency of the problems created by these diseases is the fact thatmany such diseases are age related, and thus their incidence isincreasing rapidly as population demographics change. There is a greatneed for the development of effective approaches to treatingneurodegenerative diseases and nervous system injuries, including forexample, through the inhibitors of DLK in neurons.

SUMMARY OF THE INVENTION

In one aspect the present inventions provides for compounds of Formula I(I):

or salts thereof wherein

R¹, R² and R³ are each independently H, F, Cl, Br, I, C₁₋₆ alkyl or C₁₋₆haloalkyl;

-   X¹ is N or C—R⁴, wherein R⁴ is selected from the group consisting of    —F, —Cl, —Br, I -(L¹)₀₋₁-C₁₋₆ alkyl, -(L¹)₀₋₁-C₁₋₆ haloalkyl,    -(L¹)₀₋₁-C₁₋₆ heteroalkyl, -(L²)₀₋₁-C₃₋₈ cycloalkyl, -(L²)₀₋₁-3 to 7    membered heterocycloalkyl, -(L²)₀₋₁-6-10 membered aryl,    -(L²)₀₋₁-5-10 membered heteroaryl, wherein L¹ is selected from the    group consisting of —O—, —N(H)—, —S—, —N(C₁₋₆ alkyl)-, ═O, and L² is    selected from the group consisting of —O—, —N(H)—, —N(C₁₋₆ alkyl)-,    —S—, ═O, C₁₋₄ alkylene, C₁₋₄ alkenylene, C₁₋₄ alkynylene, C₁₋₄    alkoxylene, C₁₋₄ aminoalkylene, C₁₋₄ thioalkylene and C₁₋₄    heteroalkylene, and wherein R⁴ is optionally substituted on carbon    atoms and heteroatoms with R^(R4) substituents selected from the    group consisting of F, Cl, Br, I, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3-5    membered cycloalkyl, 3-5 membered heterocycloalkyl, C₁₋₆ alkoxy,    C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ alkylthio, ═O, —NH₂, —CN,    —NO₂ and —SF₅;-   X² is N or CH;-   A is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆    haloalkyl, C₁₋₆ dialkylamino, 3 to 12 membered cycloalkyl, 3 to 12    membered heterocycloalkyl, wherein A is optionally substituted with    1-5 R^(A) substituents selected from the group consisting of F, Cl,    Br, I, —OH, —CN, —NO₂, —SF₅, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈    heteroalkyl, -(L^(A))₀₋₁-3-8 membered cycloalkyl, -(L^(A))₀₋₁-3-8    membered heterocycloalkyl, -(L^(A))₀₋₁-5 to 6 membered heteroaryl,    -(L^(A))₀₋₁-C₆ aryl, -(L^(A))₀₋₁-NR^(R1a)R^(R1b),    -(L^(A))₀₋₁-OR^(R1a), -(L^(A))₀₋₁-SR^(R1a),    -(L^(A))₀₋₁-N(R^(R1a))C(═Y¹)OR^(R1c),    -(L^(A))₀₋₁-OC(═O)N(R^(R1a))(R^(R1b)),    -(L^(A))₀₋₁-N(R^(R1a))C(═O)N(R^(R1a))(R^(R1b)),    -(L^(A))₀₋₁-C(═O)N(R^(R1a)(R^(R1a)R^(R1b)),    -(L^(A))₀₋₁-N(R^(R1a))C(═O)R^(R1b), -(L^(A))₀₋₁-C(═O)OR^(R1a),    -(L^(A))₀₋₁-OC(═O)R^(R1a), -(L^(A))₀₋₁-P(═O)(OR^(R1a))(a)(R^(R1b)),    -(L^(A))₀₋₁-S(O)₁₂R^(R1c), -(L^(A))₀₋₁-S(O)₁₂N(R^(R1a))(R^(R1b)),    -(L^(A))₀₋₁-N(R^(R1a))S(O)₁₋₂N(R^(R1a))(R^(R1b)) and    -(L^(A))₀₋₁-N(R^(R1a))S(O)₁₋₂(R^(R1c)), wherein L^(A) is selected    from the group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene,    C₁₋₄ alkoxylene, C₁₋₄ aminoalkylene, C₁₋₄ thioalkylene, C₂₋₄    alkenylene, and C₂₋₄ alkynylene; wherein R^(R1a) and R^(R1b) are    independently selected from the group consisting of hydrogen, C₁₋₈    alkyl, C₁₋₈ haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to    6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R^(R1c)    is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl,    3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered    heteroaryl and 3 to 7 membered heterocycloalkyl, and wherein R^(A)    is optionally substituted on carbon atoms and heteroatoms with    R^(RA) substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN,    —NO₂, ═O, —SF₅, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄    (halo)alkyl-C(═O)—, C₁₋₄ (halo)alkyl-S(O)₀₋₂—, C₁₋₄    (halo)alkyl-N(H)S(O)₀₋₂—, C₁₋₄(halo)alkyl-S(O)₀₋₂N(H)—,    (halo)alkyl-N(H)—S(O)₀₋₂N(H)—, C₁₋₄ (halo)alkyl-C(═O)N(H)—, C₁₋₄    (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄    (halo)alkyl-OC(═O)N(H)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—,    (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylthio,    C₁₋₄ alkylamino and C₁₋₄ dialkylamino; and-   Cy is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆    haloalkyl, 3 to 12 membered cycloalkyl, 3 to 12 membered    heterocycloalkyl, wherein Cy is optionally substituted on carbon or    heteroatoms with R^(Cy) substituents selected from the group    consisting of F, Cl, Br, I, —OH, —CN, —NO₂, —SF₅, C₁₋₈ alkyl, C₁₋₈    haloalkyl, C₁₋₈ heteroalkyl, -(L^(Cy))₀₋₁-3-8 membered cycloalkyl,    -(L^(Cy))₀₋₁-3-8 membered heterocycloalkyl, -(L^(Cy))₀₋₁-5 to 6    membered heteroaryl, -(L^(Y))₀₋₁-phenyl,    -(L^(Cy))₀₋₁-NR^(RCa)R^(RCb), -(L^(Cy))₀₋₁-OR^(RCa),    -(L^(Cy))₀₋₁-SR^(RCa), -(L^(Cy))₀₋₁-N(R^(RCa))C(═Y¹)OR^(RCc),    -(L^(Cy))₀₋₁-OC(═O)N(R^(RCa))(R^(RCb)),    -(L^(Cy))₀₋₁-N(R^(RCa))C(═O)N(R^(RCa))(R^(RCb)),    -(L^(Cy))₀₋₁-C(═O)N(R^(RCa))(R^(RCb)),    -(L^(Cy))₀₋₁-N(R^(RCa))C(═O)R^(RCb), -(L^(Cy))₀₋₁-C(═O)OR^(RCa),    -(L^(Cy))₀₋₁-OC(═O)R^(RCa), -(L^(Cy))₀₋₁-P(═O)(OR^(RCa))(OR^(RCb)),    -(L^(Cy))₀₋₁-S(O)₁₋₂R^(RCc), -(L^(Cy))₀₋₁-S(O)₁₂N(R^(RCa))(R^(RCb)),    (L^(Cy))₀₋₁-N(R^(RCa))S(O)₁₋₂N(R^(RCa))(R^(RCb)) and    -(L^(Cy))₀₋₁-N(R^(RCa))S(O)₁₋₂(R^(RCc)), wherein L^(Cy) is selected    from the group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene,    C₁₋₄ alkoxylene, C₁₋₄ aminoalkylene, C₁₋₄ thioalkylene, C₂₋₄    alkenylene, and C₂₋₄ alkynylene; wherein R^(RCa) and R^(RCb) are    independently selected from the group consisting of hydrogen, C₁₋₈    alkyl, C₁₋₈ haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to    6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R^(RCc)    is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl,    3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered    heteroaryl and 3 to 7 membered heterocycloalkyl, and wherein R^(Cy)    is optionally substituted on carbon atoms and heteroatoms with from    1 to 5 R^(RCy) substitutents selected from, F, Cl, Br, I, —NH₂, —OH,    —CN, —NO₂, ═O, —SF₅, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,    C₁₋₄(halo)alkyl-C(═O)—, C₁₋₄ (halo)alkyl-S(O)₀₋₂—, C₁₋₄    (halo)alkyl-N(H)S(O)₀₋₂—, C₁₋₄ (halo)alkyl-S(O)₀₋₂N(H)—,    (halo)alkyl-N(H)—S(O)₀₋₂N(H)—, C₁₋₄(halo)alkyl-C(═O)N(H)—,    C₁₋₄(halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄    (halo)alkyl-OC(═O)N(H)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—,    (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylthio,    C₁₋₄ alkylamino and C₁₋₄ dialkylamino.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, either A or Cy is a polycyclic carbocycle orpolycyclic heterocycle.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, either A or Cy is a bridged bicyclic carbocycleor bridged bicyclic heterocycle.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, either A or Cy is a C-linked carbocycle orC-linked heterocycle.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, X¹ is N.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, X¹ is C—R⁴.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, X² is N.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, X² is C(H).

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, R⁴ is selected from the group consisting of —F,—Cl, —CN, -(L²)₀₋₁-C₃₋₈ cycloalkyl, -(L²)₀₋₁-3 to 7 memberedheterocycloalkyl, -(L¹)₀₋₁-C₁₋₆ alkyl, -(L¹)₀₋₁-C₁₋₆ haloalkyl,-(L¹)₀₋₁-C₁₋₆ heteroalkyl, -(L²)₀₋₁-6-10 membered aryl and -(L²)₀₋₁-5-10membered heteroaryl, and is optionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, R⁴ is selected from the group consisting of —F,—Cl, C₃₋₈ cycloalkyl, 3 to 7 membered heterocycloalkyl, C₁₋₆ alkyl, C₁₋₆haloalkyl, —(O)—C₃₋₈ cycloalkyl, —(O)-3 to 7 membered heterocycloalkyl,—(O)—C₁₋₆ alkyl and —(O)—C₁₋₆ haloalkyl, and is optionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, R⁴ is selected from the group consisting ofmethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, cyclopropoxy,cyclobutoxy, cyclopentoxy, methyl, monofluoromethyl difluoromethyl,trifluoromethyl, cyclopropyl, cyclobutyl and cyclopentyl.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, R⁴ is selected from the group consisting of(L²)₀₋₁-phenyl, -(L²)₀₋₁-pyridyl, -(L²)₀₋₁-pyrimidinyl,-(L²)₀₋₁-pyrazinyl, -(L²)₀₋₁-pyridazinyl, -(L²)₀₋₁-pyrrolyl,-(L²)₀₋₁-pyrazolyl, -(L²)₀₋₁-imidazolyl, -(L²)₀₋₁-thienyl,-(L²)₀₋₁-thiazolyl and -(L²)₀₋₁-thiadiazolyl, -(L²)₀₋₁-triazoloyl,-(L²)₀₋₁-oxazolyl, -(L²)₀₋₁-oxadiazolyl, -(L²)₀₋₁-furanyl and isoptionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, R⁴ is selected from the group consisting of-(L²)₀₋₁-phenyl and -(L²)₀₋₁-pyridinyl, and is optionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, R⁴ is —OC(H)(CH₃)-phenyl wherein said phenylring is optionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, R¹, R² and R³ are each independently selectedfrom the group consisting of F, Cl, CN, hydrogen, C₁₋₄ alkyl and C₁₋₄haloalkyl.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, R¹, R² and R³ are each hydrogen.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, A and Cy are independently selected from thegroup consisting of pyrrolidine, piperidine, azetidine, azepane,piperazine, 7-azaspiro[3.5]nonane, 3,6-diazabicyclo[3.2.1]octane,2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane,octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane,2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane,3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, morpholine,hexahydro-2H-furo[3,2-c]pyrrole, 2-azabicyclo[2.1.1]hexane,2,5-diazabicyclo[2.2.1]heptane, 2-aza-tricyclo[3.3.1.1-3,7]decane,2-azabicyclo[2.1.1]hexane, 9-azabicyclo[4.2.1]nonane,9-azabicyclo[3.3.1]nonane, cyclobutane, cyclopropane, cyclopentane,2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide,2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran,8-azabicyclo[3.2.1]octane and 3-oxa-8-azabicyclo[3.2.1]octane, and isoptionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, A is selected from the group consisting ofpyrrolidine, piperidine, azetidine, azepane, piperazine, cyclopropane,cyclobutane, cyclopentane, 7-azaspiro[3.5]nonane,3-oxabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.1]octane,2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane,octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane,2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane,3-azabicyclo[3.1.0]hexane, morpholine, hexahydro-2H-furo[3,2-c]pyrroleand 2-azabicyclo[2.1.1]hexane, and is optionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, A is selected from the group consisting of2-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane,3-oxabicyclo[3.1.0]hexane, azetidine, pyrrolidine, cyclopropane,cyclobutane, cyclopentane, and is optionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, A is selected from the group consisting of(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane,(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane,(1R,5S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane,3-oxabicyclo[3.1.0]hexane, (1R,5S)-3-oxabicyclo[3.1.0]hexane,(1S,5R)-3-oxabicyclo[3.1.0]hexane,(1S,4S)-2,5-diazabicyclo[2.2.1]heptane and(1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, A is selected from the group consisting ofmethyl, ethyl, isopropyl,

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, Cy is selected from the group consisting of2,5-diazabicyclo[2.2.1]heptane, piperidine, pyrrolidine, azetidine,2-aza-tricyclo[3.3.1.1-3,7]decane, 2-oxa-5-azabicyclo[2.2.1]heptane,3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane,2-azabicyclo[2.1.1]hexane, 9-azabicyclo[4.2.1]nonane,9-azabicyclo[3.3.1]nonane, cyclobutane,2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide,2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran,8-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, and isoptionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, Cy is selected from the group consisting ofazetidine, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane,(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane,(1R,5S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane,3-oxabicyclo[3.1.0]hexane, (1R,5S)-3-oxabicyclo[3.1.0]hexane,(1S,5R)-3-oxabicyclo[3.1.0]hexane,(1S,4S)-2,5-diazabicyclo[2.2.1]heptane and(1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, Cy is a 3-12 membered carbocycle or a C-linked3-12 membered heterocycle and X² is C(H).

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, Cy is selected from the group consisting of

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, A is C₁₋₆ alkyl or C₁₋₆ dialkylamino, and isoptionally substituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, A is methyl or ethyl.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, Cy is C₁₋₆ alkyl, and is optionallysubstituted.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, A is optionally substituted with from 1 to 5R^(A) substituents selected from the group consisting of F, Cl, Br, I,—OH, —CN, —NO₂, —SF₅, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ heteroalkyl,-(L^(A))₀₋₁-3-8 membered cycloalkyl, -(L^(A))₀₋₁-3-8 memberedheterocycloalkyl, -(L^(A))₀₋₁-5 to 6 membered heteroaryl, -(L^(A))₀₋₁-C₆aryl, wherein L^(A) is selected from the group consisting of —C(O)—,—C(O)CH₂—, —OCH₂—, —CH₂O—, —CH₂—, —CH₂CH₂—, —CH₂OCH₂—, —N(H)CH₂—,—N(C₁₋₃ alkyl)CH₂—, CH₂N(H)—, —CH₂N(C₁₋₃ alkyl)-; wherein said 3-8membered cycloalkyl is selected from the group consisting of propane,butane, pentane and hexane; wherein said 3 to 8 memberedheterocycloalkyl is selected from the group consisting of oxetane,tetrahydrofuran, tetrahydropyran, oxepane, azetidine, pyrrolidine,piperidine and azepane; wherein said 5 to 6 membered heteroaryl isselected from the group consisting of pyrrole, pyrazole, imidazole,thiophene, thiazole, oxazole, trizole, pyridine, pyrimidine, pyrazine,pyridazine; wherein said C₆ aryl is phenyl; and where in R^(A) isoptionally substituted with from 1 to 5 R^(RA) substitutents selectedfrom, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, —SF₅, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄(halo)alkyl-C(═O)—, C₁₋₄(halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-N(H)S(O)₀₋₂—, C₁₋₄(halo)alkyl-S(O)₀₋₂N(H)—, (halo)alkyl-N(H)—S(O)₀₋₂N(H)—, C₁₋₄(halo)alkyl-C(═O)N(H)—, C₁₋₄ (halo)alkyl-N(H)—C(═O)—,((halo)alkyl)₂N—C(═O)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—,((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylthio, C₁₋₄ alkylamino and C₁₋₄dialkylamino.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, Cy is optionally substituted with from 1 to 5R^(Cy) substituents selected from the group consisting of F, Cl, Br, I,—OH, —CN, —NO₂, —SF₅, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ heteroalkyl,-(L^(Cy))₀₋₁-3-8 membered cycloalkyl, -(L^(Cy))₀₋₁-3-8 memberedheterocycloalkyl, -(L^(Cy))₀₋₁-5 to 6 membered heteroaryl,-(L^(Cy))₀₋₁-C₆ aryl, wherein L^(Cy) is selected from the groupconsisting of —C(O)—, —C(O)CH₂—, —OCH₂—, —CH₂O—, —CH₂—, —CH₂CH₂—,—CH₂OCH₂—, —N(H)CH₂—, —N(C₁₋₃ alkyl)CH₂—, CH₂N(H)—, —CH₂N(C₁₋₃ alkyl)-;wherein said 3-8 membered cycloalkyl is selected from the groupconsisting of propane, butane, pentane and hexane; wherein said 3 to 8membered heterocycloalkyl is selected from the group consisting ofoxetane, tetrahydrofuran, tetrahydropyran, oxepane, azetidine,pyrrolidine, piperidine and azepane; wherein said 5 to 6 memberedheteroaryl is selected from the group consisting of pyrrole, pyrazole,imidazole, thiophene, thiazole, oxazole, trizole, pyridine, pyrimidine,pyrazine, pyridazine; wherein said C₆ aryl is phenyl; and where inR^(Cy) is optionally substituted with from 1 to 5 R^(RCy) substitutentsselected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, —SF₅, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄(halo)alkyl-C(═O)—,C₁₋₄(halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-N(H)S(O)₀₋₂—, C₁₋₄(halo)alkyl-S(O)₀₋₂N(H)—, (halo)alkyl-N(H)—S(O)₀₋₂N(H)—, C₁₋₄(halo)alkyl-C(═O)N(H)—, C₁₋₄ (halo)alkyl-N(H)—C(═O)—,((halo)alkyl)₂N—C(═O)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—,((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylthio, C₁₋₄ alkylamino and C₁₋₄dialkylamino.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, Cy is optionally substituted with 1 to 5 R^(Cy)substituents selected from the group consisting of F, Cl, Br, I, CN, OH,2,3-difluorophen-1-yl-C(═O)—, 4-fluorophen-1-yl-C(═O)—,3-fluorophen-1-yl-C(═O)—, 3,5-difluorophen-1-yl-C(═O)—,3-fluoro-4-methyl-phen-1-yl-C(═O)—, 2,5-difluorophen-1-yl-C(═O)—,oxetane, oxetan-3-yl, thiazole, thiazol-2-yl, —CH₃CH₂C(═O)—, CH₃C(═O)—,CF₃CH₂—, (HO)C(CH₃)₂CH₂—, CH₃OCH₂CH₂—, CH₃OC(CH₃)₂C(═O)—, CH₃OCH₂C(═O)—,isopropyl, ethyl and methyl.

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, A is optionally substituted with 1 to 5 R^(A)substituents selected from the group consisting of F, Cl, Br, I, CN,CH₃O—, CH₃, cyclopropylmethyl, CF₃ and butyl.

one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, said compound is selected from the subformulaconsisting of

In one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, said compound is selected from the subformulaconsisting of

one embodiment of Formula I or as a sub-embodiment of any otherembodiment of Formula I, said compound is selected from the subformulaconsisting of

wherein R^(Cy) if present replaces a hydrogen atom attached to a carbonor nitrogen atom of the Cy ring.

In one embodiment of Formula I the compound is selected from the groupas set forth in Table 1.

In another aspect, the present invention provides for compositionscomprising a compound of Formula I as defined above, or any embodimentthereof and a pharmaceutically acceptable carrier, diluent or excipient.

In another aspect, the present invention provides for a method forinhibiting or preventing degeneration of a central nervous system (CNS)neuron or a portion thereof, the method comprising administering to theCNS neuron a compound of formula I. In certain embodiments, saidadministering to the CNS neuron is performed in vitro. In otherembodiments, said the method further comprises grafting or implantingthe CNS neuron into a human patient after administration of the agent.In other embodiment, said CNS neuron is present in a human patient. Inother embodiments, said administering to the CNS neuron comprisesadministration of said compound of formula I in a pharmaceuticallyacceptable carrier, diluent or excipient. In another embodiment saidadministering to the CNS neuron is carried out by an administrationroute selected from the group consisting of parenteral, subcutaneous,intravenous, intraperitoneal, intracerebral, intralesional,intramuscular, intraocular, intraarterial interstitial infusion andimplanted delivery device. In another embodiment, said method furthercomprising administering one or more additional pharmaceutical agents.In another embodiment, said administering of a compound of formula Iresults in a decrease in JNK phosphorylation, JNK activity and/or JNKexpression. In another embodiment, said the administering of a compoundof formula I results in a decrease of cJun phosphorylation, cJunactivity, and/or cJun expression. In another embodiment, said theadministering of a compound of formula I results in a decrease in p38phosphorylation, p38 activity, and/or p38 expression.

In another aspect, the present invention provides for a method forinhibiting or preventing degeneration of a central nervous system (CNS)neuron in a patient having or at risk of developing a neurodegenerativedisease or condition comprising administering to said patient atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides for a method fordecreasing or preventing one or more symptoms of a neurodegenerativedisease or condition in a patient suffering therefrom comprisingadministering to said patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides for a method fordecreasing the progression of a neurodegenerative disease or conditionin a patient suffering therefrom comprising administering to saidpatient a therapeutically effective amount of a compound of formula I ora pharmaceutically acceptable salt thereof. In certain embodiments, saidneurodegenerative disease of condition is selected from the groupconsisting of: Alzheimer's disease, Huntington's disease, Parkinson'sdisease, Parkinson's-plus diseases, amyotrophic lateral sclerosis (ALS),ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage,trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy,myasthenia gravis, muscular dystrophy, progressive muscular atrophy,primary lateral sclerosis (PLS), pseudobulbar palsy, progressive bulbarpalsy, spinal muscular atrophy, inherited muscular atrophy, invertebratedisk syndromes, cervical spondylosis, plexus disorders, thoracic outletdestruction syndromes, peripheral neuropathies, prophyria, multiplesystem atrophy, progressive supranuclear palsy, corticobasaldegeneration, dementia with Lewy bodies, frontotemporal dementia,demyelinating diseases, Guillain-Barre syndrome, multiple sclerosis,Charcot-Marie_Tooth disease, prion disease, Creutzfeldt-Jakob disease,Gerstmann-Striussler-Scheinker syndrome (GSS), fatal familial insomnia(FFI), bovine spongiform encephalopathy, Pick's disease, epilepsy, AIDSdemential complex, nerve damage caused by exposure to toxic compoundsselected from the group consisting of heavy metals, industrial solvents,drugs and chemotherapeutic agents; injury to the nervous system causedby physical, mechanical or chemical trauma, glaucoma, lattice dystrophy,retinitis pigmentosa, age-related macular degeneration (AMD),photoreceptor degeneration associated with wet or dry AMD, other retinaldegeneration, optic nerve drusen, optic neuropthy and optic neuritis. Incertain embodiment, said neurodegenerative disease of condition in apatient is selected from the group consisting of: Alzheimer's disease,Parkinson's disease, and amyotrophic lateral sclerosis (ALS), In certainembodiment, said the compound of formula I is administered incombination with one or more additional pharmaceutical agents.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions

As used herein, the term “alkyl”, by itself or as part of anothersubstituent, means, unless otherwise stated, a straight or branchedchain hydrocarbon radical, having the number of carbon atoms designated(i.e., C₁₋₈ means one to eight carbons). Examples of alkyl groupsinclude methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl,iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike. The term “alkenyl” refers to an unsaturated alkyl radical havingone or more double bonds. Similarly, the term “alkynyl” refers to anunsaturated alkyl radical having one or more triple bonds. Examples ofsuch unsaturated alkyl groups include linear and branched groupsincluding vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “cycloalkyl,”“carbocyclic,” or “carbocycle” refers to hydrocarbon ring system havingspecified overall number of ring atoms (e.g., 3 to 12 ring atoms in a 3to 12 membered cycloalkyl or C₃₋₁₂ cycloalkyl) and being fully saturatedor having no more than one double bond between ring vertices for a 3-5membered cycloalkyl and being saturated or having no more than twodouble bonds between ring vertices for 6 or larger membered cycloalkyl.The monocyclic or polycyclic ring may be optionally substituted with oneor more oxo groups. As used herein, “cycloalkyl,” “carbocyclic,” or“carbocycle” is also meant to refer to polycyclic (including fused andbridged bicyclic, fused and bridged polyclic and spirocyclic)hydrocarbon ring system such as, for example, bicyclo[2.2.1]heptane,pinane, bicyclo[2.2.2]octane, adamantane, norborene, spirocyclic C₅₋₁₂alkane, etc. As used herein, the terms, “alkenyl,” “alkynyl,”“cycloalkyl,”, “carbocycle,” and “carbocyclic,” are meant to includemono and polyhalogenated variants thereof.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chainhydrocarbon radical, consisting of the stated number of carbon atoms andfrom one to three heteroatoms selected from the group consisting of O,N, Si and S, and wherein the nitrogen and sulfur atoms can optionally beoxidized and the nitrogen heteroatom can optionally be quaternized. Theheteroatom(s) O, N and S can be placed at any interior position of theheteroalkyl group. The heteroatom Si can be placed at any position ofthe heteroalkyl group, including the position at which the alkyl groupis attached to the remainder of the molecule. A “heteroalkyl” cancontain up to three units of unsaturation, and also include mono- andpoly-halogenated variants, or combinations thereof. Examples include—CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—CF₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH═N(CH₃)—CH₃. Up to two heteroatoms can beconsecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

The term “heterocycloalkyl,” “heterocyclic,” or “heterocycle” refers toa saturated or partially unsaturated ring system radical having from theindicated number of overall number of stated ring atoms and containingfrom one to five heteroatoms selected from N, O, and S, wherein thenitrogen and sulfur atoms are optionally oxidized, nitrogen atom(s) areoptionally quaternized, as ring atoms (e.g., a 3 to 12 memberedheterocycloalkyl that would have 3 to 12 ring atoms and include at leastone heteroatom, which also could be referred to as a C₂₋₁₁heterocycloalkyl). Unless otherwise stated, a “heterocycloalkyl,”“heterocyclic,” or “heterocycle” ring system can be a monocyclic or afused, bridged, or spirocyclic polycyclic (including a fused bicyclic,bridged bicyclic or spirocyclic) ring system. The monocyclic orpolycyclic ring may be optionally substituted with one or more oxogroups. A “heterocycloalkyl,” “heterocyclic,” or “heterocycle” group canbe attached to the remainder of the molecule through one or more ringcarbons or heteroatoms. Non limiting examples of “heterocycloalkyl,”“heterocyclic,” or “heterocycle” rings include pyrrolidine, piperidine,N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam,valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide,piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone,tetrahydrofuran, tetrhydrothiophene, quinuclidine, tropane,2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane,(1s,4s)-2-azabicyclo[2.2.2]octane,(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and the like. A“heterocycloalkyl,” “heterocyclic,” or “heterocycle” can include mono-and poly-halogenated variants thereof.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—, and can be branched. Typically, an alkyl (or alkylene)group will have from 1 to 24 carbon atoms, with those groups having 10or fewer carbon atoms being preferred in the present invention.“Alkenylene” and “alkynylene” refer to the unsaturated forms of“alkylene” having double or triple bonds, respectively. “Alkylene”,“alkenylene” and “alkynylene” are also meant to include mono andpoly-halogenated variants.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —CH₂—CH═C(H)CH₂—O—CH₂— and —S—CH₂—C≡C—. The term“heteroalkylene” is also meant to include mono and poly-halogenatedvariants.

The term “alkoxylene” and “aminoalkylene” and “thioalkylene” by itselfor as part of another substituent means a divalent radical, saturated orunsaturated or polyunsaturated, derived from alkoxy, alkylamino andalkylthio, respectively, as exemplified by —OCH₂CH₂—, —O—CH₂—CH═CH—,—N(H)CH₂C(H)(CH₃)CH₂— and —S—CH₂—C≡C—. The term “alkoxylene” and“aminoalkylene” and “thioalkylene” are meant to include mono and polyhalogenated variants

The terms “alkoxy,” “alkylamino” and “alkylthio”, are used in theirconventional sense, and refer to those alkyl groups attached to theremainder of the molecule via an oxygen atom (“oxy”), an amino group(“amino”) or thio group, and further include mono- and poly-halogenatedvariants thereof. Additionally, for dialkylamino groups, the alkylportions can be the same or different.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, andthe like. The term “(halo)alkyl” as used herein includes optionallyhalogenated alkyl. Thus the term “(halo)alkyl” includes both alkyl andhaloalkyl (e.g., monohaloalkyl and polyhaloalkyl).

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon ring, which can be a single ring ormultiple rings (up to three rings) which are fused together. The term“heteroaryl” refers to aryl ring(s) that contain from one to fiveheteroatoms selected from N, O, and S, wherein the nitrogen and sulfuratoms are optionally oxidized, and the nitrogen atom(s) are optionallyquaternized. A heteroaryl group can be attached to the remainder of themolecule through a heteroatom. Non-limiting examples of aryl groupsinclude phenyl, naphthyl and biphenyl, while non-limiting examples ofheteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl,triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. Optional substituentsfor each of the above noted aryl and heteroaryl ring systems can beselected from the group of acceptable substituents described furtherbelow.

The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in someembodiments, will include both substituted and unsubstituted forms ofthe indicated radical. Preferred substituents for each type of radicalare provided below.

Substituents for the alkyl radicals (including those groups oftenreferred to as alkylene, alkenyl, alkynyl, heteroalkyl and cycloalkyl)can be a variety of groups including, but not limited to, -halogen, ═O,—OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′″C(O)NR′R″, —NR″C(O)₂R′, —NHC(NH₂)═NH,—NR′C(NH₂)═NH, —NHC(NH₂)═NR′, —NR′″C(NR′R″)═N—CN, —NR′″C(NR′R″)═NOR′,—NHC(NH₂)═NR′,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR'S(O)₂R″,—NR′″S(O)₂NR′R″, —CN, —NO₂, —(CH₂)₁₋₄—OR′, —(CH₂)₁₋₄—NR′R″,—(CH₂)₁₋₄—SR′, —(CH₂)₁₋₄—SiR′R “R′”, —(CH₂)₁₋₄—OC(O)R′,—(CH₂)₁₋₄—C(O)R′, —(CH₂)₁₋₄—CO₂R′, —(CH₂)₁₄CONR′R″, in a number rangingfrom zero to (2m′+1), where m′ is the total number of carbon atoms insuch radical. R′, R″ and R′″each independently refer groups including,for example, hydrogen, unsubstituted C₁₋₆ alkyl, unsubstitutedheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆ thioalkoxy groups, orunsubstituted aryl-C₁₋₄ alkyl groups, unsubstituted heteroaryl,substituted heteroaryl, among others. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 3-, 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant toinclude 1-pyrrolidinyl and 4-morpholinyl. Other substitutents for alkylradicals, including heteroalkyl, alkylene, include for example, ═O,═NR′, ═N—OR′, ═N—CN, ═NH, wherein R′ include substituents as describedabove. When a substituent for the alkyl radicals (including those groupsoften referred to as alkylene, alkenyl, alkynyl, heteroalkyl andcycloalkyl) contains an alkylene, alkenylene, alkynylene linker (e.g.,—(CH₂)₁₋₄—NR′R″ for alkylene), the alkylene linker includes halovariants as well. For example, the linker “—(CH₂)₁₋₄—” when used as partof a substituent is meant to include difluoromethylene,1,2-difluoroethylene, etc.

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from the group including, but not limited to,-halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′,—CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′, —NR′C(O)NR″R′″,—NHC(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″,—NR'S(O)₂R″, —N₃, perfluoro-C₁₋₄ alkoxy, and perfluoro-C₁₋₄alkyl, —(CH₂)₁₋₄—OR′, —(CH₂)₁₋₄—NR′R″, —(CH₂)₁₋₄—SR′,—(CH₂)₁₋₄—SiR′R″R′″, —(CH₂)₁₋₄—OC(O)R′, —(CH₂)₁₋₄—C(O)R′,—(CH₂)₁₋₄—CO₂R′, —(CH₂)₁₋₄CONR′R″, in a number ranging from zero to thetotal number of open valences on the aromatic ring system; and where R′,R″ and R′″ are independently selected from hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, unsubstituted aryl andheteroaryl, (unsubstituted aryl)-C₁₋₄ alkyl, and unsubstitutedaryloxy-C₁₋₄ alkyl. Other suitable substituents include each of theabove aryl substituents attached to a ring atom by an alkylene tether offrom 1-4 carbon atoms. When a substituent for the aryl or heteroarylgroup contains an alkylene, alkenylene, alkynylene linker (e.g.,—(CH₂)₁₋₄—NR′R″ for alkylene), the alkylene linker includes halovariants as well. For example, the linker “—(CH₂)₁₋₄—” when used as partof a substituent is meant to include difluoromethylene,1,2-difluoroethylene, etc.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

As used herein, the term “C-linked” means that the group that the termdescribes is attached the remainder of the molecule through a ringcarbon atom.

As used herein, the term “N-linked” means that the group that the termdescribes is attached to the remainder of the molecule through a ringnitrogen atom.

As used herein, the term “chiral” refers to molecules which have theproperty of non-superimposability of the mirror image partner, while theterm “achiral” refers to molecules which are superimposable on theirmirror image partner.

As used herein, the term “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

As used herein a wavy line “

” that intersects a bond in a chemical structure fragment indicates thepoint of attachment of the bond to which the wavy bond intersects in thechemical structure fragment to the remainder of a molecule or structuralformula.

As used herein, the representation of a group (e.g., X^(d)) inparenthesis followed by a subscript integer range (e.g., (X^(d))₀₋₂)means that the group can have the number of occurrences as designated bythe integer range. For example, (X^(d))₀₋₁ means the group X^(d) can beabsent or can occur one time.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers can separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention can contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand 1 or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer can also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which canoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

As used herein, the term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

As used herein, the term “solvate” refers to an association or complexof one or more solvent molecules and a compound of the invention.Examples of solvents that form solvates include, but are not limited to,water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,and ethanolamine. The term “hydrate” refers to the complex where thesolvent molecule is water.

As used herein, the term “protecting group” refers to a substituent thatis commonly employed to block or protect a particular functional groupon a compound. For example, an “amino-protecting group” is a substituentattached to an amino group that blocks or protects the aminofunctionality in the compound. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitable protectinggroups include acetyl and silyl. A “carboxy-protecting group” refers toa substituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups inOrganic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein, the term “mammal” includes, but is not limited to,humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,pigs, and sheep.

As used herein, the term “salts” is meant to include salts of the activecompounds which are prepared with relatively nontoxic acids or bases(e.g., those salts that are pharmaceutically acceptable), depending onthe particular substituents found on the compounds described herein.When compounds of the present invention contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredbase, either neat or in a suitable inert solvent. Examples of saltsderived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary and tertiary amines, including substitutedamines, cyclic amines, naturally-occurring amines and the like, such asarginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al., “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. As used herein the term “prodrug” refers tothose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues, is covalently joined through an amide orester bond to a free amino, hydroxy or carboxylic acid group of acompound of the present invention. The amino acid residues include butare not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁₋₆)alkanoyloxymethyl,1-((C₁₋₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁₋₆)alkanoyloxy)ethyl,(C₁₋₆)alkoxycarbonyloxymethyl, N—(C₁₋₆)alkoxycarbonylaminomethyl,succinoyl, (C₁₋₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites ofcompounds of the invention. As used herein, a “metabolite” refers to aproduct produced through metabolism in the body of a specified compoundor salt thereof. Such products can result for example from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention can exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention.

The compounds of the present invention can also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the present invention alsoembraces isotopically-labeled variants of the present invention whichare identical to those recited herein, bur the for the fact that one ormore atoms are replace by an atom having the atomic mass or mass numberdifferent from the predominant atomic mass or mass number usually foundin nature for the atom. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedin to compounds of the invention include istopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine,such as ²H (“D”), ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹³²P, ³³P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically labeled compounds of thepresent invention (e.g., those labeled with ³H or ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (³H) andcarbon-14 (¹⁴C) isotopes are usefule for their ease of preparation anddetectability. Further substituteion with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resutingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of thepresent inventions can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

The terms “treat” and “treatment” refer to both therapeutic treatmentand/or prophylactic treatment or preventative measures, wherein theobject is to prevent or slow down (lessen) an undesired physiologicalchange or disorder, such as, for example, the development or spread ofcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease or disorder, stabilized (i.e., notworsening) state of disease or disorder, delay or slowing of diseaseprogression, amelioration or palliation of the disease state ordisorder, and remission (whether partial or total), whether detectableor undetectable. “Treatment” can also mean prolonging survival ascompared to expected survival if not receiving treatment. Those in needof treatment include those already with the disease or disorder as wellas those prone to have the disease or disorder or those in which thedisease or disorder is to be prevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In some embodiments, a therapeuticallyeffective amount is an amount of a chemical entity described hereinsufficient to significantly decrease or delay neuronal cell death.

The term “administering” as used herein refers to contacting a neuron orportion therof with a compound described herein. This includesadministration of the compound to a subject (e.g., a patient, mammal) inwhich the neuron or portion therof is present, as well as introducingthe inhibitor into a medium in which a neuro or portion thereof iscultured.

The term “patient” as used herein refers to any mammal, includinghumans, higher non-human primates, rodenst domestic and farm animalssuch as cow, horses, dogs and cats. In one embodiment, the patient is ahuman patient.

The term “bioavailability” refers to the systemic availability (i.e.,blood/plasma levels) of a given amount of drug administered to apatient. Bioavailability is an absolute term that indicates measurementof both the time (rate) and total amount (extent) of drug that reachesthe general circulation from an administered dosage form.

The phrases “preventing axon degeneration,” “preventing neurondegeneration,” “preventing CNS neuron degeneration,” “inhibiting axondegeneration,” “inhibiting neuron degeneration” “inhibiting CNS neurondegeneration” as used herein include (i) the ability to inhibit orpresenve axon or neuron degeration in patients diagnosed as having aneurodegerative disease or risk of developing a neurodegenerativedisease and (ii) the ability to inhibit or prevent further axon orneuron degeneration in patients who are already suffering from, or havesymptoms of a neurodegenerative disease. Preventing axon or neurondegeneration includes decreasing or inhbiting axon or neurondegeneration, which may be characterized by complete or partialinhibition or neuron or axon degeneration. This can be assessed, forexample, by analysis of neurological function. The above-listed termsalso include in vitro and ex vivo methods. Further, the pharases“preventing neuron degeneration” and “inhibiting neuron degeneration” inclued such inhibiton with respect to the entire neuron or a portionthereof, such as the neuron ell body, axons and dendrites. Theadministration of one or more agent as described herein may result in atleast a 10% decrease (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or even 100% decrease in oneor more symptoms of a disorder of the nervous system, a condition of thenervous system that is secondary to a disease, condition, or therapyhaving a primary effect outside of the nervous system; an inusry to thenervous system caused by physical, mechanical or chemical trauma, pain;and ocular related neurodegeneration; memory loss; or a psychiatricdisorder (e.g., tremors, slowness of movement, ataxia, loss of balance,depressioin, decreased cognitive function, short term memory loss, longterm memory loss, confusion, changes in personality, languagedifficultities, loss of sensory perception, sensitivity to touch,numbness in extremities, muscle weakness, muscle paralysis, musclecramps, muscle spasms, significant changes in eating habits, excessivefear or worry, insomnia, delusions, hallucinations, fatigue, back pain,chest pain, digestive problems, headache, rapid heart rate, dizziness,blurred vision, shadows or missing areas of vision, metamorphopsia,impairment in color vision, decreased recovery of visual function afterexposure to bright light, and loss in visual contrast sensitivity) in asubject or population compared to a control subject or population thatdoes not receive the one or more agent described herein. Theadministration of one or more agent as described herein may result in atleast a 10% decrease (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100% decrease)in the number of neurons (or neuron bodies, axons, or dendrites thereof)that degenerate in a neuron population or in a subject compared to thenumber of neurons (or neuron bodies, axons, or dendrites thereof) thatdegenerate in neuron population or in a subject that is not administeredthe one or more of the agents described herein. The administration ofone or more agent as described herein may result in at least a 10%decrease (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100% decrease) in thelikelihood of developing a disorder of the nervous system; a conditionof the nervous system that is secondary to a disease, condition, ortherapy having a primary effect outside of the nervous system; an injuryto the nervous system caused by physical, mechanical, or chemicaltrauma, pain; an ocular-related neurodegeneration; memory loss; or apsychiatric disorder in a subject or a subject population compared to acontrol subject or population not treated with the one or more compoundsdescribed herein.

The term “neuron” as used herein denotes nervous system cells thatinclude a central cell body or soma, and two types of extensions orprojections: dendrites, by which, in general, the majority of neuronalsignals are conveyed to the cell body, and axons, by which, in general,the majority of neuronal signals are conveyed from the cell body toeffector cells, such as target neurons or muscle. Neurons can conveyinformation from tissues and organs into the central nervous system(afferent or sensory neurons) and transmit signals from the centralnervous systems to effector cells (efferent or motor neurons). Otherneurons, designated interneurons, connect neurons within the centralnervous system (the brain and spinal column). Certain specific examplesof neuron types that may be subject to treatment according to theinvention include cerebellar granule neurons, dorsal root ganglionneurons, and cortical neurons.

B. Compounds

In one aspect the present invention provides for novel compounds. In afirst embodiment of such compounds (Embodiment 1; abbreviated as “E1”)the invention provides for compounds of Formula I (I):

-   or salts thereof wherein-   R¹, R² and R³ are each independently H, F, Cl, Br, I, C₁₋₆ alkyl or    C₁₋₆ haloalkyl;-   X¹ is N or C—R⁴, wherein R⁴ is selected from the group consisting of    —F, —Cl, —Br, I -(L¹)₀₋₁-C₁₋₆ alkyl, -(L¹)₀₋₁-C₁₋₆ haloalkyl,    -(L¹)₀₋₁-C₁₋₆ heteroalkyl, -(L²)₀₋₁-C₃₋₈ cycloalkyl, -(L²)₀₋₁₋₃ to 7    membered heterocycloalkyl, -(L²)₀₋₁-6-10 membered aryl,    -(L²)₀₋₁-5-10 membered heteroaryl, wherein L¹ is selected from the    group consisting of —O—, —N(H)—, —S—, —N(C₁₋₆ alkyl)-, ═O, and L² is    selected from the group consisting of —O—, —N(H)—, —N(C₁₋₆ alkyl)-,    —S—, ═O, C₁₋₄ alkylene, C₁₋₄ alkenylene, C₁₋₄ alkynylene, C₁₋₄    alkoxylene, C₁₋₄ aminoalkylene, C₁₋₄ thioalkylene and C₁₋₄    heteroalkylene, and wherein R⁴ is optionally substituted on carbon    atoms and heteroatoms with R^(R4) substituents selected from the    group consisting of F, Cl, Br, I, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3-5    membered cycloalkyl, 3-5 membered heterocycloalkyl, C₁₋₆ alkoxy,    C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ alkylthio, ═O, —NH₂, —CN,    —NO₂ and —SF₅;-   X² is N or CH;-   A is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆    haloalkyl, C₁₋₆ dialkylamino, 3 to 12 membered cycloalkyl, 3 to 12    membered heterocycloalkyl, wherein A is optionally substituted with    1-5 R^(A) substituents selected from the group consisting of F, Cl,    Br, I, —OH, —CN, —NO₂, —SF₅, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈    heteroalkyl, -(L^(A))₀₋₁-3-8 membered cycloalkyl, -(L^(A))₀₋₁-3-8    membered heterocycloalkyl, -(L^(A))₀₋₁-5 to 6 membered heteroaryl,    -(L^(A))₀₁-C₆ aryl, -(L^(A))₀₋₁-NR^(R1a)R^(R1b),    -(L^(A))₀₋₁-OR^(R1a), -(L^(A))₀₋₁-SR^(R1a),    -(L^(A))₀₋₁-N(R^(R1a))C(═Y¹)OR^(R1c),    -(L^(A))₀₋₁-OC(═O)N(R^(R1a))(R^(R1b)),    -(L^(A))₀₁-N(R^(R1a))C(═O)N(R^(R1a))(R^(R1b)),    -(L^(A))₀₋₁-C(═O)N(R^(R1a)(R^(R1a))(R^(R1b)),    -(L^(A))₀₋₁-N(R^(R1a))C(═O)R^(R1b), -(L^(A))₀₋₁-C(═O)OR^(R1a),    -(L^(A))₀₋₁-OC(═O)R^(R1a), (L^(A))₀₋₁-P(═O)(OR^(R1a))(OR^(R1b)),    (L^(A))₀₋₁-S(O)₁₂R^(R1c), -(L^(A))₀₋₁-S(O)₁₂N(R^(R1a))(R^(R1b)),    -(L^(A))₀₋₁-N(R^(R1a))S(O)₁₋₂N(R^(R1a))(R^(R1b)) and    -(L^(A))₀₋₁-N(R^(R1a))S(O)₁₋₂(R^(R1c)), wherein L^(A) is selected    from the group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene,    C₁₋₄ alkoxylene, C₁₋₄ aminoalkylene, C₁₋₄ thioalkylene, C₂₋₄    alkenylene, and C₂₋₄ alkynylene; wherein R^(R1a) and R^(R1b) are    independently selected from the group consisting of hydrogen, C₁₋₈    alkyl, C₁₋₈ haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to    6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R^(R1c)    is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl,    3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered    heteroaryl and 3 to 7 membered heterocycloalkyl, and wherein R^(A)    is optionally substituted on carbon atoms and heteroatoms with    R^(RA) substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN,    —NO₂, ═O, —SF₅, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄    (halo)alkyl-C(═O)—, C₁₋₄ (halo)alkyl-S(O)₀₋₂—, C₁₋₄    (halo)alkyl-N(H)S(O)₀₋₂—, C₁₋₄ (halo)alkyl-S(O)₀₋₂N(H)—,    (halo)alkyl-N(H)—S(O)₀₋₂N(H)—, C₁₋₄ (halo)alkyl-C(═O)N(H)—, C₁₋₄    (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄    (halo)alkyl-OC(═O)N(H)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—,    (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylthio,    C₁₋₄ alkylamino and C₁₋₄ dialkylamino; and-   Cy is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆    haloalkyl, 3 to 12 membered cycloalkyl, 3 to 12 membered    heterocycloalkyl, wherein Cy is optionally substituted on carbon or    heteroatoms with R^(Cy) substituents selected from the group    consisting of F, Cl, Br, I, —OH, —CN, —NO₂, —SF₅, C₁₋₈ alkyl, C₁₋₈    haloalkyl, C₁₋₈ heteroalkyl, -(L^(Cy))₀₋₁-3-8 membered cycloalkyl,    -(L^(Cy))₀₋₁-3-8 membered heterocycloalkyl, -(L^(Cy))₀₋₁-5 to 6    membered heteroaryl, -(L^(Cy))₀₋₁-phenyl,    -(L^(Cy))₀₋₁-NR^(RCa)R^(RCb), -(L^(Cy))₀₋₁-OR^(RCa),    -(L^(Cy))₀₋₁-SR^(RCa), -(L^(Cy))₀₋₁-N(R^(RCa))C(═Y 1)OR^(RCc),    -(L^(Cy))₀₋₁-OC(═O)N(R^(RCa))(R^(RCb)),    -(L^(Cy))₀₋₁-N(R^(RCa))C(═O)N(R^(RCa))(R^(RCb)),    -(L^(Cy))₀₋₁-C(═O)N(R^(RCa))(R^(RCb)),    (L^(Cy))₀₋₁-N(R^(RCa))C(═O)R^(RCb), -(L^(Cy))₀₋₁-C(═O)OR^(RCa),    -(L^(Cy))₀₋₁-OC(═O)R^(RCa), -(L^(Cy))₀₋₁-P(═O)(OR^(RCa))(OR^(RCb)),    -(L^(Cy))₀₋₁-S(O)₁₋₂R^(RCc), -(L^(Cy))₀₋₁-S(O)₁₂N(R^(RCa))(R^(RCb)),    -(L^(Cy))₀₋₁-N(R^(RCa))S(O)₁₋₂N(R^(RCa))(R^(RCb)) and    -(L^(Cy))₀₋₁-N(R^(RCa))S(O)₁₋₂(R^(RCc)), wherein L^(Cy) is selected    from the group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene,    C₁₋₄ alkoxylene, C₁₋₄ aminoalkylene, C₁₋₄ thioalkylene, C₂₋₄    alkenylene, and C₂₋₄ alkynylene; wherein R^(RCa) and R^(RCb) are    independently selected from the group consisting of hydrogen, C₁₋₈    alkyl, C₁₋₈ haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to    6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R^(RCc)    is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl,    3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered    heteroaryl and 3 to 7 membered heterocycloalkyl, and wherein R^(Cy)    is optionally substituted on carbon atoms and heteroatoms with from    1 to 5 R^(RCy) substitutents selected from, F, Cl, Br, I, —NH₂, —OH,    —CN, —NO₂, ═O, —SF₅, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,    C₁₋₄(halo)alkyl-C(═O)—, C₁₋₄ (halo)alkyl-S(O)₀₋₂—, C₁₋₄    (halo)alkyl-N(H)S(O)₀₋₂—, C₁₋₄ (halo)alkyl-S(O)₀₋₂N(H)—,    (halo)alkyl-N(H)—S(O)₀₋₂N(H)—, C₁₋₄ (halo)alkyl-C(═O)N(H)—, C₁₋₄    (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄    (halo)alkyl-OC(═O)N(H)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—,    (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylthio,    C₁₋₄ alkylamino and C₁₋₄ dialkylamino.

Further embodiments (E) of the first embodiment of compounds of theinvention, are described below

E2. A compound according to E1, wherein either A or Cy is a polycycliccarbocycle or polycyclic heterocycle.E3. A compound according to E1 or E2, wherein X¹ is N.E4. A compound according to E1 or E2, wherein X¹ is C—R⁴.E5. A compound of claim E1, E2, E3 or E4, wherein X² is N.E6. A compound of claim, E1, E2, E3 or E4, wherein X² is C(H).E7. A compound according to claim E1, E2, E4, E5 or E6, wherein R⁴ isselected from the group consisting of —F, —Cl, —CN, -(L²)₀₋₁-C₃₋₈cycloalkyl, -(L²)₀₋₁-3 to 7 membered heterocycloalkyl, -(L¹)₀₋₁-C₁₋₆alkyl, -(L¹)₀₋₁-C₁₋₆ haloalkyl, -(L¹)₀₋₁-C₁₋₆ heteroalkyl, -(L²)₀₋₁-6-10membered aryl and -(L²)₀₋₁-5-10 membered heteroaryl, and is optionallysubstituted.E8. A compound according to claim E1, E2, E4, E5, E6 or E7, wherein R⁴is selected from the group consisting of —F, —Cl, C₃₋₈ cycloalkyl, 3 to7 membered heterocycloalkyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —(O)—C₃₋₈cycloalkyl, —(O)-3 to 7 membered heterocycloalkyl, —(O)—C₁₋₆ alkyl and—(O)—C₁₋₆ haloalkyl, and is optionally substituted.E9. A compound of claim E1, E2, E4, E5, E6, E7 or E8, wherein R⁴ isselected from the group consisting of methoxy, monofluoromethoxy,difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, tert-butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, methyl,monofluoromethyl difluoromethyl, trifluoromethyl, cyclopropyl,cyclobutyl and cyclopentyl.E10. A compound of claim E1, E2, E4, E5, E6 or E7, wherein R⁴ isselected from the group consisting of (L²)₀₋₁-phenyl, -(L²)₀₋₁-pyridyl,-(L²)₀₋₁-pyrimidinyl, -(L²)₀₋₁-pyrazinyl, -(L²)₀₋₁-pyridazinyl,-(L²)₀₋₁-pyrrolyl, -(L²)₀₋₁-pyrazolyl, -(L²)₀₋₁-imidazolyl,-(L²)₀₋₁-thienyl, -(L²)₀₋₁-thiazolyl and -(L²)₀₋₁-thiadiazolyl,-(L²)₀₋₁-triazoloyl, -(L²)₀₋₁-oxazolyl, -(L²)₀₋₁-oxadiazolyl,-(L²)₀₋₁-furanyl and is optionally substituted.E11. A compound of claim E1, E2, E4, E5, E6, E7 or E10, wherein R⁴ isselected from the group consisting of -(L²)₀₋₁-phenyl and-(L²)₀₋₁-pyridinyl, and is optionally substituted.E12. A compound of claim E1, E2, E4, E5, E6, E7, E10 or E11, wherein R⁴is —OC(H)(CH₃)-phenyl wherein said phenyl ring is optionallysubstituted.E13. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11 orE12, wherein R¹, R² and R³ are each independently selected from thegroup consisting of F, Cl, CN, hydrogen, C₁₋₄ alkyl and C₁₋₄ haloalkyl.E14. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12 or E13, wherein R¹, R² and R³ are each hydrogen.E15. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13 or E14, wherein A and Cy are independently selected from thegroup consisting of pyrrolidine, piperidine, azetidine, azepane,piperazine, 7-azaspiro[3.5]nonane, 3,6-diazabicyclo[3.2.1]octane,2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane,octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane,2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane,3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, morpholine,hexahydro-2H-furo[3,2-c]pyrrole, 2-azabicyclo[2.1.1]hexane,2,5-diazabicyclo[2.2.1]heptane, 2-aza-tricyclo[3.3.1.1-3,7]decane,2-azabicyclo[2.1.1]hexane, 9-azabicyclo[4.2.1]nonane,9-azabicyclo[3.3.1]nonane, cyclobutane, cyclopropane, cyclopentane,2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide,2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran,8-azabicyclo[3.2.1]octane and 3-oxa-8-azabicyclo[3.2.1]octane, and isoptionally substituted.E16. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14 or E15, wherein A is selected from the group consisting ofpyrrolidine, piperidine, azetidine, azepane, piperazine, cyclopropane,cyclobutane, cyclopentane, 7-azaspiro[3.5]nonane,3-oxabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.1]octane,2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane,octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane,2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane,3-azabicyclo[3.1.0]hexane, morpholine, hexahydro-2H-furo[3,2-c]pyrroleand 2-azabicyclo[2.1.1]hexane, and is optionally substituted.E17. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14, E15 or E16, wherein A is selected from the groupconsisting of 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane,3-oxabicyclo[3.1.0]hexane, azetidine, pyrrolidine, cyclopropane,cyclobutane, cyclopentane, and is optionally substituted.E18. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14, E15, E16 or E17, wherein A is selected from the groupconsisting of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane,(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane,(1R,5S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane,3-oxabicyclo[3.1.0]hexane, (1R,5S)-3-oxabicyclo[3.1.0]hexane,(1S,5R)-3-oxabicyclo[3.1.0]hexane,(1S,4S)-2,5-diazabicyclo[2.2.1]heptane and(1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally substituted.E19. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13 or E14, wherein is A is selected from the group consisting ofmethyl, ethyl, isopropyl,

E20. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14, E15, E16, E17, E18 or E19, wherein Cy is selected fromthe group consisting of 2,5-diazabicyclo[2.2.1]heptane, piperidine,pyrrolidine, azetidine, 2-aza-tricyclo[3.3.1.1-3,7]decane,2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane,3-oxabicyclo[3.1.0]hexane, 2-azabicyclo[2.1.1]hexane,9-azabicyclo[4.2.1]nonane, 9-azabicyclo[3.3.1]nonane, cyclobutane,2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide,2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran,8-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, and isoptionally substituted.E21. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14, E15, E16, E17, E18, E19 or E20, wherein Cy is selectedfrom the group consisting of azetidine,(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane,(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane,(1R,5S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane,3-oxabicyclo[3.1.0]hexane, (1R,5S)-3-oxabicyclo[3.1.0]hexane,(1S,5R)-3-oxabicyclo[3.1.0]hexane,(1S,4S)-2,5-diazabicyclo[2.2.1]heptane and(1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally substituted.E22. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13 or E14, wherein Cy is selected from the group consisting of

E23. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13 or E14, wherein A is C₁₋₆ alkyl or C₁₋₆ dialkylamino, and isoptionally substituted.E24. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13 or E14, wherein A is methyl or ethyl.E25. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13 or E14, wherein Cy is C₁₋₆ alkyl, and is optionallysubstituted.E26. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14, E15, E16, E17, E18 or E23, wherein A is optionallysubstituted with from 1 to 5 R^(A) substituents selected from the groupconsisting of F, Cl, Br, I, —OH, —CN, —NO₂, —SF₅, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ heteroalkyl, -(L^(A))₀₋₁-3-8 membered cycloalkyl,-(L^(A))₀₋₁-3-8 membered heterocycloalkyl, -(L^(A))₀₋₁-5 to 6 memberedheteroaryl, -(L^(A))₀₋₁-C₆ aryl, wherein L^(A) is selected from thegroup consisting of —C(O)—, —C(O)CH₂—,—OCH₂—, —CH₂O—, —CH₂—, —CH₂CH₂—,—CH₂OCH₂—, —N(H)CH₂—, —N(C₁₋₃ alkyl)CH₂—, CH₂N(H)—, —CH₂N(C₁₋₃ alkyl)-;wherein said 3-8 membered cycloalkyl is selected from the groupconsisting of propane, butane, pentane and hexane; wherein said 3 to 8membered heterocycloalkyl is selected from the group consisting ofoxetane, tetrahydrofuran, tetrahydropyran, oxepane, azetidine,pyrrolidine, piperidine and azepane; wherein said 5 to 6 memberedheteroaryl is selected from the group consisting of pyrrole, pyrazole,imidazole, thiophene, thiazole, oxazole, trizole, pyridine, pyrimidine,pyrazine, pyridazine; wherein said C₆ aryl is phenyl; and where in R^(A)is optionally substituted with from 1 to 5 R^(RA) substitutents selectedfrom, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, —SF₅, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄(halo)alkyl-C(═O)—, C₁₋₄(halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-N(H)S(O)₀₋₂—, C₁₋₄(halo)alkyl-S(O)₀₋₂N(H)—, (halo)alkyl-N(H)—S(O)₀₋₂N(H)—, C₁₋₄(halo)alkyl-C(═O)N(H)—, C₁₋₄ (halo)alkyl-N(H)—C(═O)—,((halo)alkyl)₂N—C(═O)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—,((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylthio, C₁₋₄ alkylamino and C₁₋₄dialkylamino.E27. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14, E15, E20, E21 or E25, wherein Cy is optionallysubstituted with from 1 to 5 R^(Cy) substituents selected from the groupconsisting of F, Cl, Br, I, —OH, —CN, —NO₂, —SF₅, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ heteroalkyl, -(L^(Cy))₀₋₁-3-8 membered cycloalkyl,-(L^(Cy))₀₋₁-3-8 membered heterocycloalkyl, -(L^(Cy))₀₋₁-5 to 6 memberedheteroaryl, -(L^(Cy))₀₋₁-C₆ aryl, wherein L^(Cy) is selected from thegroup consisting o —C(O)—, —C(O)CH₂—,—OCH₂—, —CH₂O—, —CH₂—, —CH₂CH₂—,—CH₂OCH₂—, —N(H)CH₂—, —N(C₁₋₃ alkyl)CH₂—, CH₂N(H)—, —CH₂N(C₁₋₃ alkyl)-;wherein said 3-8 membered cycloalkyl is selected from the groupconsisting of propane, butane, pentane and hexane; wherein said 3 to 8membered heterocycloalkyl is selected from the group consisting ofoxetane, tetrahydrofuran, tetrahydropyran, oxepane, azetidine,pyrrolidine, piperidine and azepane; wherein said 5 to 6 memberedheteroaryl is selected from the group consisting of pyrrole, pyrazole,imidazole, thiophene, thiazole, oxazole, trizole, pyridine, pyrimidine,pyrazine, pyridazine; wherein said C₆ aryl is phenyl; and where inR^(Cy) is optionally substituted with from 1 to 5 R^(RCy) substitutentsselected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, —SF₅, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ (halo)alkyl-C(═O)—, C₁₋₄(halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-N(H)S(O)₀₂—, C₁₋₄(halo)alkyl-S(O)₀₋₂N(H)—, (halo)alkyl-N(H)—S(O)₀₋₂N(H)—, C₁₋₄(halo)alkyl-C(═O)N(H)—, C₁₋₄ (halo)alkyl-N(H)—C(═O)—,((halo)alkyl)₂N—C(═O)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—,C₁₋₄(halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—,((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylthio, C₁₋₄ alkylamino and C₁₋₄dialkylamino.E28. A compound of claim of claim E1, E2, E3, E4, E5, E6, E7, E8, E9,E10, E11, E12, E13, E14, E15, E20, E21, E24, E25 or E26, wherein Cy isoptionally substituted with 1 to 5 R^(Cy) substituents selected from thegroup consisting of F, Cl, Br, I, CN, OH, 2,3-difluorophen-1-yl-C(═O)—,4-fluorophen-1-yl-C(═O)—, 3-fluorophen-1-yl-C(═O)—,3,5-difluorophen-1-yl-C(═O)—, 3-fluoro-4-methyl-phen-1-yl-C(═O)—,2,5-difluorophen-1-yl-C(═O)—, oxetane, oxetan-3-yl, thiazole,thiazol-2-yl, —CH₃CH₂C(═O)—, CH₃C(═O)—, CF₃CH₂—, (HO)C(CH₃)₂CH₂—,CH₃OCH₂CH₂—, CH₃OC(CH₃)₂C(═O)—, CH₃OCH₂C(═O)—, isopropyl, ethyl andmethyl.E29. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14, E15, E16, E17, E18, E23 or E26, wherein A is optionallysubstituted with 1 to 5 R^(A) substituents selected from the groupconsisting of F, Cl, Br, I, CN, CH₃O—, CH₃, cyclopropylmethyl, CF₃ andbutyl.E30. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E25, E26, E27,E28 or E29, wherein said compound is selected from the subformulaconsisting of

E31. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14, E20, E21, E22, E25, E27, E28 or E29, wherein saidcompound is selected from the subformula consisting of

E32. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,E12, E13, E14, E25, E16, E27, E18, E19, E20, E21, E22, E24, E26, E27,E28 or E29, wherein said compound is selected from the subformulaconsisting of

wherein R^(Cy) if present replaces a hydrogen atom attached to a carbonor nitrogen atom of the Cy ringE33. A compound of claim 1 selected from the group as set forth in Table1.

C. Synthesis of Compounds

Compounds of the invention as well as key intermediates can be preparedfollowing the general synthetic schemes described below (Scheme 1-4). InSchemes 1-4, R¹, R², R³, R⁴, X¹ and X² have the meaning as described forcompounds of Formula I; halo refers to a halogen atom, e.g., Cl, F, Br,I; and R where present means a cyclic or noncyclic noninterferringsustituent. More detailed description of the individual reaction steps,is found in the Examples section below. Those skilled in the art willappreciate that other synthetic routes may be used to synthesize theinventive compounds. Although specific starting materials and reagentsare depicted in the Schemes and discussed below, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

In preparing compounds of the invention, protection of remotefunctionality (e.g., primary or secondary amine) of intermediates may benecessary. The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. Suitable amino-protecting groups include acetyl,trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethylenoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, 1991.

As illustrated in Scheme 1, compounds or intermediates of the inventionscan be prepared by displacement of a halogen atom from adihalothiopyrimidine compound (i) with an amine group under basicconditions. Further treatment of the alkylthio compound (ii) underoxidative conditions provides the oxidized sulfone (iii) compound. ASuzuki-Miyaura coupling reaction between (iii) and a boronate reagent(iv) with a Pd(O) catalyst yields compounds and or intermediates of theinvention (v) (See, Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,2457-2483).

As illustrated in Scheme 2, compounds or intermediates of the inventioncan be prepared by reaction of a trihalo pyrimidine (vi) with a boronateester under Pd(O) coupling conditions to provide biheteroaryl (vii).Subsequent sequential displacement of a halogens atom of vii with an thesame of different amine reagents under basic conditions, providebiheteroaryl compounds (ix).

As illustrated in Scheme 3, compounds or intermediates of the inventioncan be prepared by Suzuki-Miyaura coupling of dichloroodopyridine (x)with an amine under Pd(0) catalyzed conditions (See, Hartwig, J. F.(1997), “Palladium-Catalyzed Amination of Aryl Halides: Mechanism andRational Catalyst Design”, Synlett 4: 329-340). Displacement of a chlorogroup in xi with an amine followed by Suzuki coupling of the resultantproduct (xii) with a boronate ester (iv-b) provides compounds and orintermediates of the invention xiii.

As illustrated in Scheme 4, compounds and or intermediates of theinvention can be prepared by treating a R substituted dichloro compound(xiv) with an amine under base conditions to produce compound xv.Subsequent treatment of compound xv under Pd(O) catalyst couplingconditions provides compounds and or intermediates of the inventions(xvi).

D. Pharmaceutical Compositions and Administrations

In addition to one or more of the compounds provided above (orstereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, (pharmaceutically acceptable) salts, or prodrugs thereof), theinvention also provides for compositions and medicaments comprising acompound of Formula I or any subformula or any embodiment thereof and atleast one pharmaceutically acceptable carrier, diluent or excipient. Thecompositions of the invention can be used for inhibiting DLK activity inpatients (e.g., humans) pharmaceutically acceptable carrier, diluent orexcipient.

The term “composition,” as used herein, is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In one embodiment, the invention provides for pharmaceuticalcompositions (or medicaments) comprising a compound of Formula I (orstereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, pharmaceutically acceptable salts, or prodrugs thereof) and apharmaceutically acceptable carrier, diluent or excipient. In anotherembodiment, the invention provides for preparing compositions (ormedicaments) comprising compounds of the invention. In anotherembodiment, the invention provides for administering compounds ofFormula I or I—I and compositions comprising compounds of Formula I orany embodiment thereof to a patient (e.g., a human patient) in needthereof.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The effective amount of the compound tobe administered will be governed by such considerations, and is theminimum amount necessary to inhibit DLK activity as required to preventor treat the undesired disease or disorder, such as for example,neurodegeneration, amyloidosis, formation of neurofibrillary tangles, orundesired cell growth. For example, such amount may be below the amountthat is toxic to normal cells, or the mammal as a whole.

In one example, the therapeutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg ofpatient body weight per day, with the typical initial range of compoundused being 0.3 to 15 mg/kg/day. The daily does is, in certainembodiments, given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. In the case of a 70 kg adulthuman, the total daily dose will generally be from about 7 mg to about1,400 mg. This dosage regimen may be adjusted to provide the optimaltherapeutic response. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, intracerebral, intraocular, intralesional orsubcutaneous administration.

The compositions comprising compounds of Formula I any embodimentthereof are normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. A typicalformulation is prepared by mixing a compound of the present inventionand a diluent, carrier or excipient. Suitable diluents, carriers andexcipients are well known to those skilled in the art and are describedin detail in, e.g., Ansel, Howard C., et al., Ansel's PharmaceuticalDosage Forms and Drug Delivery Systems. Philadelphia: Lippincott,Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: TheScience and Practice of Pharmacy. Philadelphia: Lippincott, Williams &Wilkins, 2000; and Rowe, Raymond C. Handbook of PharmaceuticalExcipients. Chicago, Pharmaceutical Press, 2005. The formulations mayalso include one or more buffers, stabilizing agents, surfactants,wetting agents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, perfuming agents, flavoring agents, diluents andother known additives to provide an elegant presentation of the drug(i.e., a compound of the present invention or pharmaceutical compositionthereof) or aid in the manufacturing of the pharmaceutical product(i.e., medicament).

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water and the like. The particularcarrier, diluent or excipient used will depend upon the means andpurpose for which a compound of the present invention is being applied.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations can also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Aactive pharmaceutical ingredient of the invention (e.g., compound ofFormula I or any embodiment thereof) can also be entrapped inmicrocapsules prepared, for example, by coacervation techniques or byinterfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philidelphia, Pa.

Sustained-release preparations of a compound of the invention (e.g.,compound of Formula I or any embodiment thereof) can be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I or an embodiment thereof, which matrices are inthe form of shaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983),non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater.Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers suchas the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate) andpoly-D-(−)-3-hydroxybutyric acid (EP 133,988A). Sustained releasecompositions also include liposomally entrapped compounds, which can beprepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci.U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A.77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A).Ordinarily, the liposomes are of the small (about 200-800 Angstroms)unilamelar type in which the lipid content is greater than about 30 mol% cholesterol, the selected proportion being adjusted for the optimaltherapy.

The formulations include those suitable for the administration routesdetailed herein. The formulations can conveniently be presented in unitdosage form and can be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21st Edition, Lippincott Williams &Wilkins, Philidelphia, Pa. Such methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients.

In general the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers,diluents or excipients or finely divided solid carriers, diluents orexcipients, or both, and then, if necessary, shaping the product. Atypical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. The formulations can beprepared using conventional dissolution and mixing procedures. Forexample, the bulk drug substance (i.e., compound of the presentinvention or stabilized form of the compound (e.g., complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more of the excipientsdescribed above. A compound of the present invention is typicallyformulated into pharmaceutical dosage forms to provide an easilycontrollable dosage of the drug and to enable patient compliance withthe prescribed regimen.

In one example, compounds of Formula I or any embodiment thereof may beformulated by mixing at ambient temperature at the appropriate pH, andat the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a galenical administration form. The pHof the formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of Formula I or an embodimentthereof is formulated in an acetate buffer, at pH 5. In anotherembodiment, the compounds of Formula I or an embodiment thereof aresterile. The compound may be stored, for example, as a solid oramorphous composition, as a lyophilized formulation or as an aqueoussolution.

Formulations of a compound of the invention (e.g., compound of Formula Ior an embodiment thereof) suitable for oral administration can beprepared as discrete units such as pills, capsules, cachets or tabletseach containing a predetermined amount of a compound of the invention.

Compressed tablets can be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets can bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets canoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs can be prepared for oral use. Formulationsof a compound of the invention (e.g., compound of Formula I or anembodiment thereof) intended for oral use can be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients can be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets can be uncoated or can be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax can be employed.

An example of a suitable oral administration form is a tablet containingabout 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250mg, 300 mg and 500 mg of the compound of the invention compounded withabout 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose,about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving the compound, for example5-400 mg, of the invention in a suitable buffer solution, e.g. aphosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride,if desired. The solution may be filtered, e.g., using a 0.2 micronfilter, to remove impurities and contaminants.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientcan be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients can be formulated in a creamwith an oil-in-water cream base.

If desired, the aqueous phase of the cream base can include a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol (including PEG 400) and mixtures thereof. Thetopical formulations can desirably include a compound which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethyl sulfoxide and related analogs.

The oily phase of the emulsions of this invention can be constitutedfrom known ingredients in a known manner. While the phase can comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

Aqueous suspensions of a compound of the invention (e.g., compound ofFormula I or an embodiment thereof) contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

Formulations of a compound of the invention (e.g., compound of Formula Ior I-I) can be in the form of a sterile injectable preparation, such asa sterile injectable aqueous or oleaginous suspension. This suspensioncan be formulated according to the known art using those suitabledispersing or wetting agents and suspending agents which have beenmentioned above. The sterile injectable preparation can also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, such as a solution in 1,3-butanediol orprepared as a lyophilized powder. Among the acceptable vehicles andsolvents that can be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables.

The amount of active ingredient that can be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans cancontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which can varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion can contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which can contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which can include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration can be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration can beprepared according to conventional methods and can be delivered withother therapeutic agents such as compounds heretofore used in thetreatment of disorders as described below.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

When the binding target is located in the brain, certain embodiments ofthe invention provide for a compound of formula I (or an embodimentthereof) to traverse the blood-brain barrier. Certain neurodegenerativediseases are associated with an increase in permeability of theblood-brain barrier, such that a compound of formula I (or an embodimentthereof) can be readily introduced to the brain. When the blood-brainbarrier remains intact, several art-known approaches exist fortransporting molecules across it, including, but not limited to,physical methods, lipid-based methods, and receptor and channel-basedmethods.

Physical methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, circumventing the blood-brain barrier entirely, or bycreating openings in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injectioninto the brain (see, e.g., Papanastassiou et al., Gene Therapy9:398-406, 2002), interstitial infusion/convection-enhanced delivery(see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91 :2076-2080,1994), and implanting a delivery device in the brain (see, e.g., Gill etal., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

Pharmaceutical). Methods of creating openings in the barrier include,but are not limited to, ultrasound (see, e.g., U.S. Patent PublicationNo. 2002/0038086), osmotic pressure (e.g., by administration ofhypertonic mannitol (Neuwelt, E. A., Implication of the Blood-BrainBarrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y.,1989)), and permeabilization by, e.g., bradykinin or permeabilizer A-7(see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and5,686,416).

Lipid-based methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, encapsulating the a compound of formula I or I-I (or anembodiment thereof) in liposomes that are coupled to antibody bindingfragments that bind to receptors on the vascular endothelium of theblood-brain barrier (see, e.g., U.S. Patent Application Publication No.2002/0025313), and coating a compound of formula I (or an embodimentthereof) in low-density lipoprotein particles (see, e.g., U.S. PatentApplication Publication No. 2004/0204354) or apolipoprotein E (see,e.g., U.S. Patent Application Publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of formulaI (or an embodiment thereof) across the blood-brain barrier include, butare not limited to, using glucocorticoid blockers to increasepermeability of the blood-brain barrier (see, e.g., U.S. PatentApplication Publication Nos. 2002/0065259, 2003/0162695, and2005/0124533); activating potassium channels (see, e.g., U.S. PatentApplication Publication No. 2005/0089473), inhibiting ABC drugtransporters (see, e.g., U.S. Patent Application Publication No.2003/0073713); coating a compound of formula I or I-I (or an embodimentthereof) with a transferrin and modulating activity of the one or moretransferrin receptors (see, e.g., U.S. Patent Application PublicationNo. 2003/0129186), and cationizing the antibodies (see, e.g., U.S. Pat.No. 5,004,697).

For intracerebral use, in certain embodiments, the compounds can beadministered continuously by infusion into the fluid reservoirs of theCNS, although bolus injection may be acceptable. The inhibitors can beadministered into the ventricles of the brain or otherwise introducedinto the CNS or spinal fluid. Administration can be performed by use ofan indwelling catheter and a continuous administration means such as apump, or it can be administered by implantation, e.g., intracerebralimplantation of a sustained-release vehicle. More specifically, theinhibitors can be injected through chronically implanted cannulas orchronically infused with the help of osmotic minipumps. Subcutaneouspumps are available that deliver proteins through a small tubing to thecerebral ventricles. Highly sophisticated pumps can be refilled throughthe skin and their delivery rate can be set without surgicalintervention. Examples of suitable administration protocols and deliverysystems involving a subcutaneous pump device or continuousintracerebroventricular infusion through a totally implanted drugdelivery system are those used for the administration of dopamine,dopamine agonists, and cholinergic agonists to Alzheimer's diseasepatients and animal models for Parkinson's disease, as described byHarbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al.,Mov. Disord. 2: 143, 1987.

A compound of formula I (or an embodiment thereof) used in the inventionare formulated, dosed, and administered in a fashion consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. A compound of formula I (or anembodiment thereof) need not be, but is optionally formulated with oneor more agent currently used to prevent or treat the disorder inquestion. The effective amount of such other agents depends on theamount of a compound of the invention present in the formulation, thetype of disorder or treatment, and other factors discussed above.

These are generally used in the same dosages and with administrationroutes as described herein, or about from 1 to 99% of the dosagesdescribed herein, or in any dosage and by any route that isempirically/clinically determined to be appropriate.

For the prevention or treatment of disease, the appropriate dosage of acompound of formula I or I-I (or an embodiment thereof) (when used aloneor in combination with other agents) will depend on the type of diseaseto be treated, the properties of the compound, the severity and courseof the disease, whether the compound is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the compound, and the discretion of the attendingphysician. The compound is suitably administered to the patient at onetime or over a series of treatments. Depending on the type and severityof the disease, about 1 μg/kg to 15 mg/kg (e.g., 0.1 mg/kg-10 mg/kg) ofcompound can be an initial candidate dosage for administration to thepatient, whether, for example, by one or more separate administrations,or by continuous infusion. One typical daily dosage might range fromabout 1 μg kg to 100 mg/kg or more, depending on the factors mentionedabove. For repeated administrations over several days or longer,depending on the condition, the treatment would generally be sustaineduntil a desired suppression of disease symptoms occurs. One exemplarydosage of a compound of formula I (or an embodiment thereof) would be inthe range from about 0.05 mg/kg to about 10 mg/kg. Thus, one or moredoses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg (or anycombination thereof) may be administered to the patient. Such doses maybe administered intermittently, e.g., every week or every three weeks(e.g., such that the patient receives from about two to about twenty,or, e.g., about six doses of the antibody). An initial higher loadingdose, followed by one or more lower doses may be administered. Anexemplary dosing regimen comprises administering an initial loading doseof about 4 mg/kg, followed by a weekly maintenance dose of about 2 mg kgof the compound. However, other dosage regimens may be useful. Theprogress of this therapy is easily monitored by conventional techniquesand assays.

Other typical daily dosages might range from, for example, about 1 g/kgto up to 100 mg/kg or more (e.g., about 1 μg kg to 1 mg/kg, about 1μg/kg to about 5 mg/kg, about 1 mg kg to 10 mg/kg, about 5 mg/kg toabout 200 mg/kg, about 50 mg/kg to about 150 mg/mg, about 100 mg/kg toabout 500 mg/kg, about 100 mg/kg to about 400 mg/kg, and about 200 mg/kgto about 400 mg/kg), depending on the factors mentioned above.Typically, the clinician will administer a compound until a dosage isreached that results in improvement in or, optimally, elimination of,one or more symptoms of the treated disease or condition. The progressof this therapy is easily monitored by conventional assays. One or moreagent provided herein may be administered together or at different times(e.g., one agent is administered prior to the administration of a secondagent). One or more agent may be administered to a subject usingdifferent techniques (e.g., one agent may be administered orally, whilea second agent is administered via intramuscular injection orintranasally). One or more agent may be administered such that the oneor more agent has a pharmacologic effect in a subject at the same time.Alternatively, one or more agent may be administered, such that thepharmacological activity of the first administered agent is expiredprior the administration of one or more secondarily administered agents(e.g., 1, 2, 3, or 4 secondarily administered agents).

E. Indications and Methods of Treatment

In another aspect, the invention provides for methods of inhibiting theDual Leucine Zipper Kinase (DLK) in an in vitro (e.g., a nerve graft ofnerve transplant) or in vivo setting (e.g., in a patient) by contactingDLK present in an in vitro or in vivo setting with compounds of FormulaI or an embodiment thereof. In these methods of the invention, theinhibition of DLK signaling or expression with a compound of formula Ior an embodiment thereof results in a downstream decrease in JNKphosphorylation (e.g., a decrease in JNK2 and/or JNK3 phosphorylation),JNK activity (e.g., a decrease in JNK2 and/or JNK3 activity), and/or JNKexpression (e.g., a decrease in JNK2 and/or JNK3 expression).Accordingly, administering one or more compounds of Formula I or anembodiment thereof according to the methods of the invention can resultin decrease in activity of kinase targets downstream of the DLKsignalling cascade, e.g, (i) a decrease in JNK phosphorylation, JNKactivity, and/or JNK expression, (ii) a decrease in cJunphosphorylation, cJun activity, and/or cJun expression, and/or (iii) adecrease in p38 phosphorylation, p38 activity, and/or p38 expression.

Compounds of the invention can be used in methods for inhibiting neuronor axon degeneration. The inhibitors are, therefore, useful in thetherapy of, for example, (i) disorders of the nervous system (e.g.,neurodegenerative diseases), (ii) conditions of the nervous system thatare secondary to a disease, condition, or therapy having a primaryeffect outside of the nervous system, (iii) injuries to the nervoussystem caused by physical, mechanical, or chemical trauma, (iv) pain,(v) ocular-related neurodegeneration, (vi) memory loss, and (vii)psychiatric disorders. Non-limiting examples of some of these diseases,conditions, and injuries are provided below.

Examples of neurodegenerative diseases and conditions that can beprevented or treated according to the invention include amyotrophiclateral sclerosis (ALS), trigeminal neuralgia, glossopharyngealneuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy,progressive muscular atrophy, primary lateral sclerosis (PLS),pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy,progressive bulbar palsy, inherited muscular atrophy, invertebrate disksyndromes (e.g., herniated, ruptured, and prolapsed disk syndromes),cervical spondylosis, plexus disorders, thoracic outlet destructionsyndromes, peripheral neuropathies, prophyria, mild cognitiveimpairment, Alzheimer's disease, Huntington's disease, Parkinson'sdisease, Parkinson's-plus diseases (e.g., multiple system atrophy,progressive supranuclear palsy, and corticobasal degeneration), dementiawith Lewy bodies, frontotemporal dementia, demyelinating diseases (e.g.,Guillain-Barre syndrome and multiple sclerosis), Charcot-Marie-Toothdisease (CMT; also known as Hereditary Motor and Sensory Neuropathy(HMSN), Hereditary Sensorimotor Neuropathy (HSMN), and Peroneal MuscularAtrophy), prion disease (e.g., Creutzfeldt-Jakob disease,Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia(FFI), and bovine spongiform encephalopathy (BSE, commonly known as madcow disease)), Pick's disease, epilepsy, and AIDS demential complex(also known as HIV dementia, HIV encephalopathy, and HIV-associateddementia).

The methods of the invention can also be used in the prevention andtreatment of ocular-relatcd neurodegeneration and related diseases andconditions, such as glaucoma, lattice dystrophy, retinitis pigmentosa,age-related macular degeneration (AMD), photoreceptor degenerationassociated with wet or dry AMD, other retinal degeneration, optic nervedrusen, optic neuropathy, and optic neuritis. Non-limiting examples ofdifferent types of glaucoma that can be prevented or treated accordingto the invention include primary glaucoma (also known as primaryopen-angle glaucoma, chronic open-angle glaucoma, chronic simpleglaucoma, and glaucoma simplex), low-tension glaucoma, primaryangle-closure glaucoma (also known as primary closed-angle glaucoma,narrow-angle glaucoma, pupil-block glaucoma, and acute congestiveglaucoma), acute angle-closure glaucoma, chronic angle-closure glaucoma,intermittent angle-closure glaucoma, chronic open-angle closureglaucoma, pigmentary glaucoma, exfoliation glaucoma (also known aspseudoexfoliative glaucoma or glaucoma capsulare), developmentalglaucoma (e.g., primary congenital glaucoma and infantile glaucoma),secondary glaucoma (e.g., inflammatory glaucoma (e.g., uveitis and Fuchsheterochromic iridocyclitis)), phacogenic glaucoma (e.g., angle-closureglaucoma with mature cataract, phacoanaphylactic glaucoma secondary torupture of lens capsule, phacolytic glaucoma due to phacotoxic meshworkblockage, and subluxation of lens), glaucoma secondary to intraocularhemorrhage (e.g., hyphema and hemolytic glaucoma, also known aserythroclastic glaucoma), traumatic glaucoma (e.g., angle recessionglaucoma, traumatic recession on anterior chamber angle, postsurgicalglaucoma, aphakic pupillary block, and ciliary block glaucoma),neovascular glaucoma, drug-induced glaucoma (e.g., corticosteroidinduced glaucoma and alpha-chymotrypsin glaucoma), toxic glaucoma, andglaucoma associated with intraocular tumors, retinal deatchments, severechemical burns of the eye, and iris atrophy.

Examples of types of pain that can be treated according to the methodsof the invention include those associated with the following conditions:chronic pain, fibromyalgia, spinal pain, carpel tunnel syndrome, painfrom cancer, arthritis, sciatica, headaches, pain from surgery, musclespasms, back pain, visceral pain, pain from injury, dental pain,neuralgia, such as neuogenic or neuropathic pain, nerve inflammation ordamage, shingles, herniated disc, torn ligament, and diabetes.

Certain diseases and conditions having primary effects outside of thenervous system can lead to damage to the nervous system, which can betreated according to the methods of the present invention. Examples ofsuch conditions include peripheral neuropathy and neuralgia caused by,for example, diabetes, cancer, AIDS, hepatitis, kidney dysfunction,Colorado tick fever, diphtheria, HIV infection, leprosy, lyme disease,polyarteritis nodosa, rheumatoid arthritis, sarcoidosis, Sjogrensyndrome, syphilis, systemic lupus erythematosus, and amyloidosis.

In addition, the methods of the invention can be used in the treatmentof nerve damage, such as peripheral neuropathy, which is caused byexposure to toxic compounds, including heavy metals (e.g., lead,arsenic, and mercury) and industrial solvents, as well as drugsincluding chemotherapeutic agents (e.g., vincristine and cisplatin),dapsone, HIV medications (e.g., Zidovudine, Didanosine. Stavudine,Zalcitabine, Ritonavir, and Amprenavir), cholesterol lowering drugs(e.g., Lovastatin, Indapamid, and Gemfibrozil), heart or blood pressuremedications (e.g., Amiodarone, Hydralazine, Perhexiline), andMetronidazole.

The methods of the invention can also be used to treat injury to thenervous system caused by physical, mechanical, or chemical trauma. Thus,the methods can be used in the treatment of peripheral nerve damagecaused by physical injury (associated with, e.g., burns, wounds,surgery, and accidents), ischemia, prolonged exposure to coldtemperature (e.g., frost-bite), as well as damage to the central nervoussystem due to, e.g., stroke or intracranial hemorrhage (such as cerebralhemorrhage).

Further, the methods of the invention can be used in the prevention ortreatment of memory loss such as, for example, age-related memory loss.Types of memory that can be affected by loss, and thus treated accordingto the invention, include episodic memory, semantic memory, short-termmemory, and long-term memory. Examples of diseases and conditionsassociated with memory loss, which can be treated according to thepresent invention, include mild cognitive impairment, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, chemotherapy,stress, stroke, and traumatic brain injury (e.g., concussion).

The methods of the invention can also be used in the treatment ofpsychiatric disorders including, for example, schizophrenia, delusionaldisorder, schizoaffective disorder, schizopheniform, shared psychoticdisorder, psychosis, paranoid personality disorder, schizoid personalitydisorder, borderline personality disorder, anti-social personalitydisorder, narcissistic personality disorder, obsessive-compulsivedisorder, delirium, dementia, mood disorders, bipolar disorder,depression, stress disorder, panic disorder, agoraphobia, social phobia,post-traumatic stress disorder, anxiety disorder, and impulse controldisorders (e.g., kleptomania, pathological gambling, pyromania, andtrichotillomania).

In addition to the in vivo methods described above, the methods of theinvention can be used to treat nerves ex vivo, which may be helpful inthe context of nerve grafts or nerve transplants. Thus, the inhibitorsdescribed herein can be useful as components of culture media for use inculturing nerve cells in vitro.

Accordingly, in another aspect, the invention provides for a method forinhibiting or preventing degeneration of a central nervous system (CNS)neuron or a portion thereof, the method comprising administering to theCNS neuron a compound of formula I or an embodiment thereof.

In one embodiment, of the method for inhibiting or preventingdegeneration of a central nervous system neuron or a portion thereof,the administering to the CNS neuron is performed in vitro.

In another embodiment, of the method for inhibiting or preventingdegeneration of a central nervous system neuron or a portion thereof,the method further comprises grafting or implanting the CNS neuron intoa human patient after administration of the agent.

In another embodiment, of the method for inhibiting or preventingdegeneration of a central nervous system neuron or a portion thereof,the CNS neuron is present in a human patient.

In another embodiment, of the method for inhibiting or preventingdegeneration of a central nervous system neuron or a portion thereof,the administering to the CNS neuron comprises administration of saidcompound of formula I or an embodiment thereof in a pharmaceuticallyacceptable carrier, diluent or excipient.

In another embodiment, of the method for inhibiting or preventingdegeneration of a central nervous system neuron or a portion thereof,the administering to the CNS neuron is carried out by an administrationroute selected from the group consisting of parenteral, subcutaneous,intravenous, intraperitoneal, intracerebral, intralesional,intramuscular, intraocular, intraarterial interstitial infusion andimplanted delivery device.

In another embodiment, of the method for inhibiting or preventingdegeneration of a central nervous system neuron or a portion thereof,the method further comprises administering one or more additionalpharmaceutical agents.

The inhibitors can be optionally combined with or administered inconcert with each other or other agents known to be useful in thetreatment of the relevant disease or condition. Thus, in the treatmentof ALS, for example, inhibitors can be administered in combination withRiluzole (Rilutek), minocycline, insulin-like growth factor 1 (IGF-1),and/or methylcobalamin. In another example, in the treatment ofParkinson's disease, inhibitors can be administered with L-dopa,dopamine agonists (e.g., bromocriptine, pergolide, pramipexole,ropinirole, cabergoline, apomorphine, and lisuride), dopa decarboxylaseinhibitors (e.g., levodopa, benserazide, and carbidopa), and/or MAO-Binhibitors (e.g., selegiline and rasagiline). In a further example, inthe treatment of Alzheimer's disease, inhibitors can be administeredwith acetylcholinesterase inhibitors (e.g., donepezil, galantamine, andrivastigmine) and/or NMDA receptor antagonists (e.g., memantine). Thecombination therapies can involve concurrent or sequentialadministration, by the same or different routes, as determined to beappropriate by those of skill in the art. The invention also includespharmaceutical compositions and kits comprising combinations asdescribed herein.

In addition to the combinations noted above, other combinations includedin the invention are combinations of inhibitors of degeneration ofdifferent neuronal regions. Thus, the invention includes combinations ofagents that (i) inhibit degeneration of the neuron cell body, and (ii)inhibit axon degeneration. For example, inhibitors of GSK andtranscription are found to prevent degeneration of neuron cell bodies,while inhibitors of EGFR and p38 MAPK are found to prevent degenerationof axons. Thus, the invention includes combinations of inhibitors of GSKand EGFR (and/or p38 MAPK), combinations of transcription inhibitors andEGF (and/or p38 MAPK), and further combinations of inhibitors of dualleucine zipper-bearing kinase (DLK), glycogen synthase kinase 3β (GSK3),p38 MAPK, EGFF, phosphoinositide 3-kinase (PI3K), cyclin-dependentkinase5 (cdk5), adenylyl cyclase, c-Jun N-terminal kinase (JNK),BCL2-associated X protein (Bax), In channel,calcium/calmodulin-dependent protein kinase kinase (CaMKK), a G-protein,a G-protein coupled receptor, transcription factor 4 (TCF4), andβ-catenin. The inhibitors used in these combinations can be any of thosedescribed herein, or other inhibitors of these targets as described inWO 2011/050192, incorporated herein by reference.

The combination therapy can provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect can be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect can be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes,separate pills or capsules, or in separate infusions. In general, duringalternation therapy, an effective dosage of each active ingredient isadministered sequentially, i.e., serially, whereas in combinationtherapy, effective dosages of two or more active ingredients areadministered together.

F. Examples

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention. These examples are not intended to limit thescope of the present invention, but rather to provide guidance to askilled artisan to prepare and use the compounds, compositions, andmethods of the present invention. While particular embodiments of thepresent invention are described, the skilled artisan will appreciatethat various changes and modifications can be made without departingfrom the spirit and scope of the invention.

The chemical reactions in the Examples described can be readily adaptedto prepare a number of other compounds of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-exemplified compounds according to the invention can be successfullyperformed by modifications apparent to those skilled in the art, e.g.,by appropriately protecting interferring groups, by utilizing othersuitable reagents known in the art other than those described, and/or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.Accordingly, the following examples are provided to illustrate but notlimit the invention.

In the Examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Commercially availablereagents were purchased from suppliers such as Aldrich Chemical Company,Lancaster, TCI or Maybridge, and were used without further purificationunless otherwise indicated. The reactions set forth below were donegenerally under a positive pressure of nitrogen or argon or with adrying tube (unless otherwise stated) in anhydrous solvents, and thereaction flasks were typically fitted with rubber septa for theintroduction of substrates and reagents via syringe. Glassware was ovendried and/or heat dried. Column chromatography was conducted on aBiotage system (Manufacturer: Dyax Corporation) having a silica gelcolumn or on a silica SEP PAK® cartridge (Waters); or alternativelycolumn chromatography was carried out using on an ISCO chromatographysystem (Manufacturer: Teledyne ISCO) having a silica gel column. ¹H NMRspectra were recorded on a Varian instrument operating at 400 MHz. ¹HNMR spectra were obtained in deuterated CDCl₃, d₆-DMSO, CH₃OD ord₆-acetone solutions (reported in ppm), using tetramethylsilane (TMS) asthe reference standard (0 ppm). When peak multiplicities are reported,the following abbreviations are used: s (singlet), d (doublet), t(triplet), q (quartet), m (multiplet), br (broadened), dd (doublet ofdoublets), dt (doublet of triplets). Coupling constants, when given, arereported in Hertz (Hz).

When possible, product formed in the reaction mixtures were monitored byLC/MS. High Pressure Liquid Chromatography—Mass Spectrometry (LCMS)experiments. Example conditions for analysis include monitoring on anAgilent 1200 Series LC coupled to a 6140 quadrupole mass spectrometerusing a Supelco Ascentis Express C18 column with a linear gradient of5%-95% acetonitrile/water (with 0.1% trifluoroacetic acid in each mobilephase) within 1.4 minutes and held at 95% for 0.3 minute, or on a PESciex API 150 EX using a Phenomenex DNYC monolithic C18 column with alinear gradient of 5%-95% acetonitrile/water (with 0.1% trifluoroaceticacid in each mobile phase) within 5 minutes and held at 95% for 1 minuteto determine retention times (R_(T)) and associated mass ions.

All abbreviations used to described reagents, reaction conditions, orequipment used are consistent with the definitions set forth in the“List of standard abbreviations and acronyms” published yearly by theJournal of Organic Chemistry (an American Chemical Society journal). Thechemical names of discrete compounds of the invention were obtainedusing the structure naming features of commonly used programs includingChemBioDraw Version 11.0, Accelrys' Pipeline Pilot IUPAC compound namingprogram.

Example 1

Method A

2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5′-bipyrimidin]-2′-amine

Step 1: Synthesis of(1S,4S)-5-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]-heptane

The mixture of 4,6-dichloro-2-(methylthio)pyrimidine (450 mg, 2.31mmol), DIEA (894 mg, 6.92 mmol) and 2-oxa-5-azabicyclo[2.2.1]heptane(328 mg, 2.42 mmol) in DMF (5 mL) was stirred at 50° C. for 12 h. Water(20 mL) was added to and extracted with ethyl acetate (2×20 mL). Theorganic layers were dried over Na₂SO₄, filtered and concentrated to give(1S,4S)-5-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-oxa-5-azabicyclo-[2.2.1]heptane(550 mg, 92.5% yield) as a white solid, which was used for next stepwithout further purification LCMS (ESI): [MH]⁺=258.0.

Step 2: Synthesis of(1S,4S)-5-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-oxa-5-azabicyclo-[2.2.1]heptane

To a mixture of (1S,4S)-5-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane(550 mg, 2.13 mmol) in DCM (50 mL) was added m-CPBA (1.73 g, 8.53 mmol)portionwise. The reaction mixture was stirred at room temperature for 1h. The mixture was washed with Na₂SO₃ (sat aq, 20 mL) and wasconcentrated in vacuo to afford(1S,4S)-5-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]-heptane(600 mg, 97.0% yield) as a white solid, LCMS (ESI): [MH]⁺=289.7, whichwas used for next step without further purification.

Step 3: Synthesis of6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5′-bipyrimidin]-2′-amine

To a microwave vial charged with(1S,4S)-5-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]-heptane(600 mg, 2.07 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (641mg, 2.90 mmol), potassium acetate (284 mg, 2.90 mmol) and sodiumcarbonate (307 mg, 2.90 mmol) in acetonitrile/water (1 (5:1, 6.0 mL) wasadded PdCl₂{PtBu₂(Ph-p-NMe₂)}₂ (147 mg, 0.21 mmol) under nitrogen. Thevial was sealed and heated by microwave irradiation at 140° C. for 40min. The reaction mixture was concentrated in vacuo, and resultingresidue was purified by flash column chromatography (5% methanol indichloromethane) to provide6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5′-bipyrimidin]-2′-amine(380 mg, 52.7% yield). LCMS (ESI): [MH]⁺=349.0.

Step 4: Synthesis of 2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5′-bipyrimidin]-2′-amine

To the mixture of6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5′-bipyrimidin]-2′-amine(380 mg, 1.09 mmol) and potassium carbonate (754 mg, 5.45 mmol) in DMSO(5 mL) was added 2-azabicyclo[2.1.1]hexane hydrochloride (326 mg, 2.73mmol). The mixture was stirred at 100° C. for 5 h. After removal of thesolvent, the residue was purified by Prep-HPLC (formic acid) to afford2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5′-bipyrimidin]-2′-amine(220 mg, 57% yield). LCMS (ESI): [MH]⁺=352.1; ¹H NMR (400 MHz, DMSO-d6)δ 8.91 (s, 2H), 7.00 (s, 2H), 6.30-6.10 (m, 1H), 5.10-4.90 (m, 1H), 4.83(d, J=6.4 Hz, 1H), 4.70-4.64 (m, 1H), 3.78-3.76 (m, 1H), 3.66-3.64 (m,1H), 3.45-3.38 (m, 4H), 2.89-2.87 (m, 1H), 1.93-1.86 (m, 4H), 1.32-1.31(m, 2H).

Method B:

Step 1: Synthesis of5-(2,6-dichloropyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine

To a microwave vial charged with 2,4,6-trichloropyrimidine (300 mg, 1.64mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine(518 mg, 1.80 mmol) and cesium carbonate (1.07 g, 3.27 mmol) inacetonitrile/water (4:1, 30 mL) was added1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (60 mg,0.05 mmol) under nitrogen. The mixture was stirred at room temperaturefor 16 h. The reaction mixture was concentrated in vacuo, and resultingresidue was purified by flash column chromatography (15% ethyl acetatein petroleum ether to 50% ethyl acetate in petroleum ether) to provide5-(2,6-dichloropyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (300mg, 59.3% yield). LCMS (ESI): [MH]⁺=308.7.

Step 2: Synthesis of (1S,4S)-tert-butyl5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

To a solution of5-(2,6-dichloropyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (300mg, 0.84 mmol) in tetrahydrofuran (60 mL) was added (1S,4S)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate hydrochloride (197 mg, 0.84mmol) and N-ethyl-N-isopropylpropan-2-amine (2 mL). The mixture washeated at 75° C. for 3 h. After cooling to room temperature, water (50mL) was added to. The mixture was extracted with ethyl acetate (3×30mL). The organic layer was dried over sodium sulfate, concentrated andpurified by flash column chromatography (25% ethyl acetate in petroleumether to 100% ethyl acetate) to provide (1S,4S)-tert-butyl5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(220 mg, 48.1% yield). TLC (Thin layer chromatography) (petroleum ether(PE): ethyl acetate (EA)=3:1, R_(f)=0.3˜0.4).

Step 3: Synthesis of (1S,4S)-tert-butyl5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

To a solution of (1S,4S)-tert-butyl5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(220 mg, 0.47 mmol) in DMSO (2 mL) was added 2-azabicyclo[2.1.1]hexanehydrochloride (68 mg, 0.56 mmol) and potassium carbonate (130 mg, 0.93mmol). The mixture was heated at 90° C. for 16 h. After cooling to roomtemperature, water (50 mL) was added to. The mixture was extracted withethyl acetate (30 mL (3 times)). The organic layer was dried over sodiumsulfate, concentrated and purified by flash column chromatography (50%ethyl acetate in petroleum ether to 100% ethyl acetate) to provide(1S,4S)-tert-butyl5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(130 mg, 53.7% yield). LCMS (ESI): [MH]⁺=518.0.

Step 4: Synthesis of5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine

To an ice-cooled solution of (1S,4S)-tert-butyl5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(130 mg, 0.25 mmol) in dichloromethane (6 mL) was added trifluoroaceticacid (3 mL). The mixture was stirred at room temperature for 0.5 h.After removal of the solvent, the residue was dissolved with water (30mL), basified and extracted with dichloromethane (3×30 mL). The organiclayer was dried over sodium sulfate, concentrated to provide5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine(80 mg, 75.0% yield). LCMS (ESI): [MH]⁺=417.9.

Step 5: Synthesis of 1-((1S,4S)-5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethanone

To a solution of5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine(80 mg, 0.22 mmol) in DMSO (2 mL) was added acetic anhydride (46 mg,0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.1 mL). The mixturewas stirred at room temperature for 25 min. The mixture was concentratedin vacuum and the residue was purified by Prep-HPLC (BASE) to provide1-((1S,4S)-5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethanone(46.34 mg, 40.0% yield). LCMS (ESI): [MH]⁺=459.9; ¹H NMR (400 MHz,DMSO-d6) δ 8.91 (s, 1H), 8.36 (s, 1H), 6.79 (s, 2H), 6.53-6.21 (m, 1H),5.10-4.89 (m, 1H), 4.80-4.78 (m, 1H), 4.74-4.63 (m, 1H), 3.55-3.51 (m,1H), 3.44-3.35 (m, 2H), 3.23-2.84 (m, 4H), 2.82 (s, 1H), 2.00 (s, 1H),1.91 (s, 3H), 1.83-1.81 (m, 2H), 1.29 (d, J=2.0 Hz, 2H).

Method C:

(1R,5 S,6r)-tert-butyl6-(2′-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5′-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

Step 1: Synthesis of (1R,5S,6r)-tert-butyl6-(3-ethoxy-3-oxopropanoy)-3-azaicyclo[3.1.0]hexane-3-carboxylate

To a solution of(1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (2 g, 8.8 mmol) in acetonitrile (150 mL) was added1,1′-carbonyldiimidazole (1.71 g, 10.56 mmol). After stirring at 20° C.for 1 h, magnesium chloride (827 mg, 8.8 mmol) and potassium3-ethoxy-3-oxopropanoate (1.5 g, 8.8 mmol) was added to and the reactionmixture was stirred at 20° C. for 16 h. The reaction solution wasfiltered, concentrated and purified by flash column (60% ethyl acetatein petroleum ether) to afford (1R,5S,6r)-tert-butyl6-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.5g, 57.7% yield). ¹H NMR (400 MHz, Chloroform-d) δ 4.21-4.16 (m, 2H),3.66-3.64 (m, 1H), 3.54 (s, 3H), 3.42-3.90 (m, 2H), 2.15-2.13 (m, 2H),1.90-1.88 (m, 1H), 1.42 (s, 9H), 1.28-1.24 (m, 3H)

Step 2: Synthesis of (1R,5S,6r)-tert-butyl6-(6-hydroxy-2-mercaptopyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

The mixture of (1R,5S,6r)-tert-butyl6-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (7.6g, 25.6 mmol), carbamimidothioic acid (7.77 g, 102.3 mmol) and sodiummethanolate (5.52 g, 102.3 mmol) in anhydrous methonal (250 mL) wasrefluxed under N₂ for 16 h. After removal of the solvent, the residuewas adjusted pH to 6 with hydrogen chloride aqueous solution (2 M). Themixture was filtered and the solid was the desired product of(1R,5S,6r)-tert-butyl6-(6-hydroxy-2-mercaptopyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(7 g, 88.6% yield). ¹H NMR (400 MHz, DMSO-d6) δ 12.30 (d, J=13.6 Hz,2H), 5.45 (s, 1H), 3.57-3.53 (m, 2H), 3.33-3.29 (m, 2H), 2.05-1.99 (m,2H), 1.58-1.57 (m, 1H), 1.39 (s, 9H).

Step 3: Synthesis of (1R,5S,6r)-tert-butyl6-(6-hydroxy-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To the solution of (1R,5S,6r)-tert-butyl6-(6-hydroxy-2-mercaptopyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(7 g, 22.65 mmol) in sodium hydroxide aqueous solution (8%) was addediodomethane (6.43 g, 45.3 mmol). The resulting solution was stirred atroom temperature for 1 h. The reaction mixture was adjusted pH=5-6 withhydrogen chloride aqueous solution (2 M). The mixture was filtered andthe solid was the desired product of (1R,5S,6r)-tert-butyl6-(6-hydroxy-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(6 g, crude, about 65%, 53.4% yield). LCMS (ESI): [MH]⁺=324.1.

Step 4: Synthesis of (1R,5 S,6r)-tert-butyl6-(6-chloro-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of (1R,5S,6r)-tert-butyl6-(6-hydroxy-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(6 g, 18.57 mmol, 65%) in dry dichloromethane (250 mL) was added oxalyldichloride (2.83 g, 22.3 mmol) and DMF (0.5 mL) at 0° C. The mixture wasstirred at 0° C. for 2 h and was poured into ice water including Et₃N.The mixture was extracted with dichloromethane (250 mL*2). The organiclayer was washed with brine (100 mL), dried over sodium sulfate,concentrated and purified by flash column chromatography (20% ethylacetate in petroleum ether) to afford (1R,5S,6r)-tert-butyl6-(6-chloro-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(3.8 g, 92.7% yield).

Step 5: Synthesis of (1R,5S,6r)-tert-butyl6-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of (1R,5S,6r)-tert-butyl6-(6-chloro-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(800 mg, 2.35 mmol) in anhydrous dichloromethane (40 mL) was addedm-CPBA (2 g, 11.7 mmol). The reaction mixture was stirred at roomtemperature for 1 h. The mixture was extracted with dichloromethane(2×50 mL). The organic layer was washed with brine (50 mL), dried oversodium sulfate, concentrated and purified by flash column chromatography(30% ethyl acetate in petroleum ether) to provide (1R,5 S,6r)-tert-butyl6-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(700 mg, 80% yield)¹H NMR (400 MHz, Chloroform-d) δ 7.40 (s, 1H),3.82-3.70 (m, 2H), 3.54-3.50 (m, 2H), 3.33 (s, 3H), 2.38 (s, 2H),1.96-1.94 (m, 1H), 1.47 (s, 1H).

Step 6: Synthesis of (1R,5S,6r)-tert-butyl6-(2′-amino-2-(methylsulfonyl)-[4,5′-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a microwave vial charged with (1R,5S,6r)-tert-butyl6-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(820 mg, 2.2 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (972 mg, 4.4mmol), and cesium carbonate (1.43 g, 4.4 mmol) in dioxane/water (5:1, 15mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (161 mg, 0.22 mmol) under nitrogen. The vial was sealed andheated by microwave irradiation at 110° C. for 30 min. The reactionmixture was concentrated in vacuo, and resulting residue was purified byflash column chromatography (25% ethyl acetate in petroleum ether to100% ethyl acetate) to provide (1R,5S,6r)-tert-butyl6-(2′-amino-2-(methylsulfonyl)-[4,5′-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(700 mg, 94.7% yield) LCMS (ESI): [MH]⁺=432.8.

Step 7: Synthesis of (1R,5 S,6r)-tert-butyl6-(2′-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5′-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of (1R,5S,6r)-tert-butyl6-(2′-amino-2-(methylsulfonyl)-[4,5′-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.46 mmol) in DMSO (15 mL) was added 2-azabicyclo[2.1.1]hexanehydrochloride (109.5 mg, 0.92 mmol) and potassium carbonate (127 mg,0.92 mmol). The mixture was stirred at 120° C. for 2 h. After cooling toroom temperature, the mixture was extracted with ethyl acetate (2×20mL). The organic layer was concentrated and purified by flash columnchromatography (75% ethyl acetate in petroleum ether) to provide(1R,5S,6r)-tert-butyl6-(2′-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5′-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(140 mg, 70% yield). TLC (EA, R_(f)=0.3-0.4).

Step 8: Synthesis of 2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-[4,5′-bipyrimidin]-2′-amine

To an ice-cooled solution of (1R,5S,6r)-tert-butyl6-(2′-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5′-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(120 mg, 0.276 mmol) in dichloromethane (6 mL) was added trifluoroaceticacid (3 mL). The mixture was warmed to room temperature. After 3 h, thereaction mixture was concentrated in vacuo to provide2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-[4,5′-bipyrimidin]-2′-amine (90 mg,97.3% yield). The resulting residue was used without furtherpurification. TLC (EA, R_(f)=0).

Step 9: Synthesis of 1-((1R,5S,6r)-6-(2′-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5′-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethanone

To a solution of 2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-[4,5′-bipyrimidin]-2′-amine (80 mg,0.24 mmol) and N-ethyl-N-isopropylpropan-2-amine (62 mg, 0.48 mmol) indichloromethane (15 mL) was added acetic anhydride (49 mg, 0.48 mmol).The mixture was stirred at room temperature for 30 min. After removal ofthe solvent, the residue was purified by PR-HPLC (BASE) to provide1-((1R,5S,6r)-6-(2′-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5′-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethanone(88 mg, 97.2% yield). LCMS (ESI): [MH]⁺=377.8; ¹H NMR (400 MHz,Chloroform-d) δ 8.94 (s, 2H), 6.65 (s, 1H), 5.49 (s, 2H), 4.95 (d, J=6.0Hz, 1H), 3.97 (d, J=12.0 Hz, 1H), 3.72 (s, 2H), 3.54 (s, 3H), 2.95 (s,1H), 2.30 (s, 2H), 2.06 (s, 3H), 2.00 (s, 2H), 1.70 (s, 1H), 1.45 (s,2H).

Method D:

Preparation of5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine

Step 1: Synthesis of(1S,4S)-5-(2,6-dichloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

To a microwave vial charged with 2,6-dichloro-4-iodopyridine (100 mg,0.37 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (49.19 mg, 0.44mmol) and cesium carbonate (66.29 mg, 0.48 mmol) in dioxane (5 mL) wasadded Pd₂(dba)₃ (3.5 mg, 0.048 mmol) and xantphos (3.5 mg, 0.048 mmol)under nitrogen. The vial was sealed and heated by microwave irradiationat 140° C. for 1 h. The reaction mixture was concentrated in vacuo, andresulting residue was purified by TLC (PE:EA=2:1) to afford(1S,4S)-5-(2,6-dichloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane(40 mg, 35% yield).

Step 2: Synthesis of(1S,4S)-5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-chloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

To a microwave vial charged with(1S,4S)-5-(2,6-dichloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane(100 mg, 0.41 mmol) and 2-azabicyclo[2.1.1]hexane hydrochloride (244 mg,2.04 mmol) in NMP (3 mL) was added cesium carbonate (1.33 g, 4.08 mmol).The vial was sealed and heated by microwave irradiation at 150° C. for18 h. The reaction mixture was concentrated in vacuo, and resultingresidue was purified by TLC (PE:EA=1:1) to afford compound 5 (80 mg,77.7% yield). LCMS (ESI) [MH]⁺=291.8.

Step 3: Synthesis of5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine

To a microwave vial charged with(1S,4S)-5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-chloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane(70 mg, 0.24 mmol),3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(75.53 mg, 0.26 mmol) and potassium carbonate (66.29 mg, 0.48 mmol) indioxane/water (5:1, 3.0 mL) was added1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (3.5 mg,0.048 mmol) under nitrogen. The vial was sealed and heated by microwaveirradiation at 120° C. for 1 h. The reaction mixture was concentrated invacuo, and resulting residue was purified by PR-HPLC (Basic) to afford5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine(24.55 mg, 24.6% yield). LCMS (ESI) [MH]⁺=416.1; ¹H NMR (400 MHz,DMSO-d6) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.15 (t, J=74.0 Hz, 1H), 6.42 (s,1H), 6.21 (s, 2H), 5.54 (s, 1H), 4.76-4.74 (m, 2H), 4.62 (s, 1H), 3.73(d, J=6.8 Hz, 1H), 3.63 (d, J=7.6 Hz, 1H), 3.45 (d, J=8.8 Hz, 1H), 3.33(s, 2H), 3.10 (d, J=10.4 Hz, 1H), 2.88-2.86 (m, 1H), 1.88-1.81 (m, 4H),1.27-1.26 (m, 2H).

Method E:

Step 1—Synthesis of(1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane(70929-339-C)

To a solution of 4,6-dichloro-2-methylsulfonyl-pyrimidine (3.41 g, 15mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (2.03g, 15.0 mmol) in N,N-dimethylacetamide (40.5 mL), was addedN,N-diisopropylethylamine (6.60 mL). The resulting mixture was stirredat room temperature. After 30 min, the reaction mixture was concentratedto a solid. The crude material was purified by column chromatographyusing an 80 g column, with a gradient of 0% to 100% ethyl acetate inheptane. The combined fractions containing product were concentratedunder reduced pressure to provide(1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane(3.03 g). 1H NMR (400 MHz, Chloroform-d) δ 6.30 (s, 1H), 3.98-3.81 (m,3H), 3.45-3.35 (m, 2H), 3.28 (s, 3H), 2.16-1.98 (m, 2H), 1.95-1.86 (m,1H).

Step 2—Synthesis of6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5′-bipyrimidin]-2′-amine(70929-339-E)

To a solution of(1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane(500 mg, 1.73 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (382mg, 1.73 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (63.8 mg,0.0863 mmol) in acetonitrile (6.90 mL) was added potassium acetate inwater (3.45 mL) in a microwave vial equipped with a stirbar. The mixturewas microwaved at 110° C. for 5 min. The solid was and washed with ethylacetate (5 mL) filtered under vacuum, providing6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5′-bipyrimidin]-2′-amine(598 mg, crude). 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=5.6, 2.8 Hz,2H), 7.40-6.97 (m, 1H), 7.28 (s, 2H), 5.14 (d, J=16.0 Hz, 1H), 4.76 (d,J=27.9 Hz, 1H), 3.82 (d, J=7.7, 1.5 Hz, 1H), 3.76-3.66 (m, 1H),3.60-3.51 (m, 1H), 3.50-3.41 (m, 1H), 3.35 (d, J=6.1 Hz, 3H), 1.95 (d,J=22.0 Hz, 2H).

Step 3—Synthesis of2-(azetidin-1-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5′-bipyrimidin]-2′-amine

5-[2-methylsulfonyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine(30.0 mg, 0.861 mmol), azetidine hydrochloride (24.7 mg, 0.258 mmol),potassium carbonate (71.4 mg, 0.517 mmol), and 1-methyl-2-pyrrolidinone(0.861 mL) were combined in a reaction flask and heated to 130° C. for16 hrs. The reaction was filtered and purified by reverse phase columnchromatography using a gradient of 20% to 60% acetonitrile in 0.1%ammonium hydroxide in water. The combined fractions containing productwere concentrated under reduced pressure to provide2-(azetidin-1-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5′-bipyrimidin]-2′-amine.1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 6.97 (s, 2H), 4.95 (s, 1H),4.66 (s, 1H), 3.99 (t, J=7.5 Hz, 4H), 3.77 (dd, J=7.3, 1.5 Hz, 1H), 3.64(d, J=7.3 Hz, 1H), 3.43 (dd, J=10.5, 1.5 Hz, 1H), 3.40-3.32 (m, 1H),3.17 (s, 1H), 2.24 (p, J=7.5 Hz, 2H), 1.85 (s, 2H).

Method F:

Preparation of6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5′-(trifluoromethyl)-[2,3′-bipyridin]-6′-amine

Step 1: Synthesis of 2,6-dichloro-4-(piperidin-4-yl)pyridine

To a solution of tert-butyl4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylate (2 g, 6.06 mmol) inDCM(2 mL) was added TFA (3 mL). The solution was stirred at roomtemperature for 30 min. The reaction solution was concentrated to afford2,6-dichloro-4-(piperidin-4-yl)pyridine as TFA salt, which was usedwithout further purification. LCMS (ESI) [MH]+=231.1.

Step 2: Synthesis of2,6-dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine

A solution of 2,6-dichloro-4-(piperidin-4-yl)pyridine (2 g, 8.7 mmol)and oxetan-3-one (6.26 g, 87 mmol) in THF (50 mL) was stirred at 70° C.for 30 min and then sodium cyanoborohydride (2.74 g, 43.5 mmol) wasadded to the mixture and the mixture solution was stirred at 70° C. foradditional 30 min. The reaction solution was filtered and the filtratewas concentrated to give crude product which was purified by flashcolumn chromatography on silica gel (30% ethyl acetate in petroleumether) to afford 2,6-dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine.(2 g, 88.7% yield). LCMS (ESI) [MH]+=286.7.

Step 3: Synthesis of2-chloro-6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine

A mixture of 2,6-dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine (450mg, 1.57 mmol), 3-methoxyazetidine hydrochloride (963 mg, 7.83 mmol) andDIPEA (3 mL, 16.9 mmol) in DMSO (5 mL) was stirred at 100° C. for 16 h.The mixture was poured into water and extracted with EtOAc. The organiclayer was washed with brine, dried over Na2SO4, evaporated and purifiedby flash column chromatography on silica gel (30% ethyl acetate inpetroleum ether) to give2-chloro-6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine(320 mg, 60.3% yield). LCMS (ESI) [MH]+=337.8

Step 4: Synthesis of6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5′-(trifluoromethyl)-[2,3′-bipyridin]-6′-amine

To a solution of2-chloro-6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine(80 mg, 0.24 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine(140 mg, 0.48 mmol) and cesium carbonate (160 mg, 0.48 mmol) indioxane/H2O (5:1, 4 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18 mg, 0.024 mmol)under nitrogen. The mixture was irradiated by microwave at 110° C. for30 min. The reaction mixture was filtered, the filtrate was concentratedand purified by Prep-HPLC to afford6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5′-(trifluoromethyl)-[2,3′-bipyridin]-6′-amine(68.3 mg 61.5%, yield). LCMS (ESI) [MH]+=464, 1HNMR (400 MHz, CDCl3), δ8.745 (s, 1H), δ8.363 (s, 1H), δ8.232 (s, 1H), δ8.832 (s, 1H), δ6.109(s, 1H), δ5.642 (s, 2H), δ4.74-4.67 (m, 4H),δ 4.39-4.22 (m, 3H), δ3.94-3.90 (m, 2H), δ 3.63-3.56 (m, 1H), δ 3.346 (s, 3H), δ 2.980 (d,J=10.8 Hz, 2H), δ 2.55-2.46 (m, 1H), δ 2.06-1.99 (m, 1H), δ 1.93-1.87(m, 4H). LCMS:464.0 (M+1).

Method G:

6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5′-(trifluoromethyl)-[2,3′-bipyridin]-6′-amineStep 1: 1-(2,6-dichloro-4-pyridyl)cyclobutanecarbonitrile

To a stirring solution of 2,4,6-trichloropyridine (1.00 g, 5.48 mmol)and cyclobutanecarbonitrile (0.53 mL, 5.5 mmol) in anhydrous THF (27 mL)at −78° C. and under nitrogen was added lithium bis(trimethylsilyl)amide(6.0 mL, 6.0 mmol, 1.0 M solution in THF). The cooling bath was removedand stirring continued for 1 h. The reaction was quenched by theaddition of sat. aq. NH₄Cl, extracted with CH₂Cl₂ and organics driedover MgSO₄. Following concentration, the reaction residue was purifiedby flash column chromatography (100:0 heptanes/EtOAc—85:15heptanes/EtOAc) to afford the title compound as a white solid (0.995 g,76%); ¹H NMR (400 MHz, CDCl₃) δ 7.34 (s, 2H), 2.92-2.80 (m, 2H),2.68-2.40 (m, 3H), 2.23-2.08 (m, 1H).

Step 21-[2-(2-aminopyrimidin-5-yl)-6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-pyridyl]cyclobutanecarbonitrile

To a solution of 1-(2,6-dichloro-4-pyridyl)cyclobutanecarbonitrile (100mg, 0.440 mmol) in anhydrous DMSO (0.44 mL) was added2-azabicyclo[2.1.1]hexane hydrochloride (60 mg, 0.48 mmol) and potassiumcarbonate (122 mg, 0.881 mmol). The vessel was sealed and the reactionmixture stirred at 100° C. for 92 h. After cooling to rt, the mixturewas diluted with diethyl ether and washed with water (2×), brine (lx)and dried over MgSO₄ and concentrated to dryness. The followingcompounds were added to the crude product: 2-aminopyridine-5-boronicacid pinacol ester (110 mg, 0.48 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (16.6 mg, 0.0220 mmol),2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (21.4 mg, 0.0440mmol), and potassium phosphate tribasic (289 mg, 1.32 mmol). Under astream of nitrogen, anhydrous, degassed THF (1.3 mL) and degassed water(0.22 mL) were added and the vial was sealed tightly. The reactionmixture was stirred at 80° C. for 3 h, cooled to rt, and filteredthrough Celite, rinsing with CH₂Cl₂. The residue obtained afterconcentration was purified by RPLC to afford the title compound as awhite solid (85.4 mg, 58% over 2 steps); ¹H NMR (400 MHz, DMSO) δ 8.92(s, 2H), 7.10 (d, J=1.1 Hz, 1H), 6.91 (br s, 2H), 6.46 (d, J=1.1 Hz,1H), 4.95-4.81 (m, 1H), 3.44 (s, 2H), 3.01-2.90 (m, 1H), 2.75-2.64 (m,4H), 2.39-2.18 (m, 1H), 2.11-1.92 (m, 3H), 1.41-1.27 (m, 2H).

Method H:

[3-[6-[2-amino-4-(trifluoromethyl)pyrimidin-5-yl]-2-methyl-pyrimidin-4-yl]-1-piperidyl]-phenyl-methanone

A solution of tert-butyl3-(6-chloro-2-methyl-pyrimidin-4-yl)piperidine-1-carboxylate (40 mg,0.13 mmol, 1.00 equiv),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine(40 mg, 0.14 mmol, 1.10 equiv) and[1,1′-BIS(DIPHENYLPHOSPHINO)FERROCENE]DICHLOROPALLADIUM(II) (10 mg,0.013 mmol, 0.1 equiv) in Acetonitrile (1.0 mL) was mixed with 1Mpotassium carbonate solution in water (420 uL, 0.42 mmol, 3.2 equiv) andstirred at 90° C. for 2 hr. The reaction mixture was extracted with DCM(3 mL) and H2O (2 mL). The organic phase was removed, dried over sodiumsulfate, and passed through a filter. The resulting organic phase wasconcentrated under vacuum. The crude product was mixed with methanol(1.0 mL) and 4M hydrogen chloride in dioxane (325 uL, 1.3 mmol, 10equiv). The resulting solution was stirred at room temperatureovernight. The reaction mixture was concentrated under vacuum. Asolution of crude product, benzoic acid (15 mg, 0.13 mmol, 1.0 equiv),HBTU (50 mg, 0.13 mmol, 1.0 equiv) and Triethylamine (90 uL, 0.65 mmol,5.0 equiv) in DMF (1.0 mL) was stirred at room temperature overnight.The reaction mixture was concentrated under vacuum and the crude productwas purified by Prep-HPLC (Column, Sunfire C18 19×150; mobile phase,CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV 254 nm) togive 21.8 mg (38%) of

[3-[6-[2-amino-4-(trifluoromethyl)pyrimidin-5-yl]-2-methyl-pyrimidin-4-yl]-1-piperidyl]-phenyl-methanone as an off white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s,1H), 7.66 (s, 2H), 7.46-7.42 (m, 3H), 7.42-7.36 (m, 2H), 7.01 (s, 1H),4.65-4.37 (m, 1H), 4.08 (q, J=5.3 Hz, 1H), 3.77-3.51 (m, 1H), 3.17 (d,J=5.3 Hz, 2H), 3.14-2.89 (m, 3H), 2.10-2.02 (m, 1H), 1.91-1.50 (m, 3H).

Method I:

1-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]cyclobutanecarbonitrileStep 1: 1-(2,6-dichloropyrimidin-4-yl)cyclobutanecarbonitrile

To a stirring solution of 2,4,6-trichloropyrimidine (1.00 g, 5.45 mmol)and cyclobutanecarbonitrile (0.53 mL, 5.5 mmol) in anhydrous THF (27 mL)at −78° C. and under nitrogen was added lithium bis(trimethylsilyl)amide(6.0 mL, 6.0 mmol, 1.0 M solution in THF) over 3 min. The cooling bathwas removed after 5 further min, and stirring continued for 3 h. Thereaction was quenched by the addition of sat. aq. NH₄Cl, extracted withCH₂Cl₂ and organics dried over MgSO₄. Following concentration, thereaction residue was purified by flash column chromatography (100:0heptanes/EtOAc—85:15 heptanes/EtOAc) to afford the title compound as acolorless solid (0.147 g, 12%); ¹H NMR (400 MHz, CDCl₃) δ 7.54 (s, 1H),2.97-2.82 (m, 2H), 2.82-2.67 (m, 2H), 2.51-2.35 (m, 1H), 2.35-2.16 (m,1H).

Step 21-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]cyclobutanecarbonitrile

Into a vial was weighed1-(2,6-dichloropyrimidin-4-yl)cyclobutanecarbonitrile (64.2 mg, 0.281mmol), 2-aminopyridine-5-boronic acid pinacol ester (64.2 mg, 0.281mmol), tetrakis(triphenylphosphine)palladium(0) (16.3 mg, 5 mol %), andsodium carbonate (90 mg, 0.84 mmol). Under a stream of nitrogen,anhydrous, degassed THF (0.84 mL) and degassed water (0.14 mL) wereadded and the vial was sealed tightly. The reaction mixture was stirredat 90° C. for 68 h, cooled to rt, filtered through Celite rinsing withCH₂Cl₂, and concentrated to dryness. To this crude product was added2-azabicyclo[2.1.1]hexane hydrochloride (49 mg, 0.39 mmol),N,N-diisopropylethylamine (0.147 mL, 0.844 mmol), and anhydrous DMF (1.1mL). The vessel was sealed and the reaction mixture stirred at 80° C.for 4.5 h. After cooling to rt, the mixture was concentrated and theresidue subjected to RPLC purification to yield the title compound as awhite solid (36.9 mg, 39% over 2 steps); ¹H NMR (400 MHz, DMSO) δ 8.69(s, 1H), 8.05 (s, 1H), 7.23 (t, J=74.0 Hz, 2H), 7.20 (s, 1H), 6.70 (brs, 2H), 4.95 (m, 1H), 3.54 (s, 2H), 2.99-2.91 (m, 1H), 2.81 (m, 2H),2.72-2.60 (m, 2H), 2.32-2.18 (m, 1H), 2.13-1.94 (m, 3H), 1.45-1.38 (m,2H).

Method J:

Step 1: tert-butyl 3-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylate

Under a nitrogen atmosphere, zinc dust (6.91 g, 105 mmol) was suspendedin N,N-dimethylacetamide (10 mL) and 1,2-dibromoethane (1.08 mL, 12.4mmol) was added, followed by careful addition of trimethylsilylchloride(1.61 mL, 12.4 mmol) and was added cautiously over 5 min while the flasksat on a bed of ice. The bath was removed, and after stirring for afurther 15 min, a solution of N-(tert-butoxycarbonyl)-3-iodoazetidine(25.1 g, 86.9 mmol) in N,N-dimethylacetamide (30 mL) was added over 30min and stirring was continued for an additional 30 min. In the openatmosphere, this mixture was filtered through Celite as quickly aspossible, rinsing with N,N-dimethylacetamide (100 mL). The resultingyellow solution was injected into a separately prepared, nitrogenflushed vessel containing[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.56 g, 3.10mmol), copper(I) iodide (1.18 g, 6.21 mmol) and2,6-dichloro-4-iodopyridine (17.0 g, 62.1 mmol) and this mixture wasstirred at 80° C. for 19.5 h. After cooling to rt, the mixture wasdiluted with EtOAc and washed with water (3×). On the third time,filtration through Celite was necessary to break the emulsion, followingwhich, the organics were washed with brine and then dried over MgSO₄.After being freed of volatiles, the resultant residue was purified byflash column chromatography (100:0-70:30 heptanes/EtOAc) to affordtert-butyl 3-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylate as awhite solid (10.98 g, 58%); ¹H NMR (400 MHz, CDCl₃) δ 7.22 (s, 2H), 4.35(dd, J=8.7, 5.6 Hz, 2H), 3.92 (dd, J=8.7, 5.6 Hz, 2H), 3.73-3.61 (m,1H), 1.47 (s, 9H).

Step 2: 2,6-dichloro-4-(1-(oxetan-3-yl)azetidin-3-yl)pyridine

A solution of tert-butyl3-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylate (0.940 g, 3.10 mmol)in trifluoroacetic acid (3.1 mL) was stirred for 1 h, and thenconcentrated to dryness to afford the TFA salt as a white solid. Thesolid was re-suspended in anhydrous THF (12.4 mL) and submitted to theaction of triethylamine (2.62 mL, 18.6 mmol) and 3-oxetanone (0.60 mL,9.3 mmol). After stirring for 10 min, sodium triacetoxyborohydride (2.07g, 9.30 mmol) was added and stirring continued for 18.5 h at 35° C. Thereaction mixture was diluted with CH₂Cl₂ and washed with sat. aq. NaHCO₃and organics dried over MgSO₄. Concentration gave sufficiently pure2,6-dichloro-4-(1-(oxetan-3-yl)azetidin-3-yl)pyridine as a yellow liquid(640 mg, 80% over 2 steps); ¹H NMR (400 MHz, CDCl₃) δ 7.27 (s, 2H), 4.72(dd, J=6.5, 5.3 Hz, 2H), 4.54 (dd, J=6.5, 5.3 Hz, 2H), 3.82-3.77 (m,1H), 3.77-3.71 (m, 2H), 3.67-3.58 (m, 1H), 3.32-3.27 (m, 2H).

Step 3:6-cyclopropyl-5′-(difluoromethoxy)-4-(1-(oxetan-3-yl)azetidin-3-yl)-[2,3′-bipyridin]-6′-amine

A vial was charged with2,6-dichloro-4-(1-(oxetan-3-yl)azetidin-3-yl)pyridine (133 mg, 0.513mmol), palladium(II) acetate (5.8 mg, 5 mol %),butyldi-1-adamantylphosphine (14.5 mg, 7.5 mol %), potassiumcyclopropyltrifluoroborate (79.9 mg, 0.523 mmol), and cesium carbonate(502 mg, 1.54 mmol) and purged under nitrogen before the addition ofdegassed toluene (2.6 mL) and deionized water (0.25 mL). The mixture wasstirred at 110° C. overnight and then cooled to rt. To the mixture wasadded3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(220 mg, 0.770 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (38.7 mg, 0.0513 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (50.0 mg, 0.103mmol), and potassium phosphate tribasic monohydrate (366 mg, 1.54 mmol).The vial was purged with nitrogen gas, sealed, and stirred at 110° C.for 2 h. After cooling to rt, the mixture was concentrated to dryness.The reaction residue thus obtained was purified by flash columnchromatography (100:0-80:20 CH₂Cl₂/MeOH) and by RPLC to afford the titlecompound as a white solid (22.9 mg, 12% over 2 steps); ¹H NMR (400 MHz,DMSO) δ 8.53 (d, J=1.9 Hz, 1H), 7.94 (s, 1H), 7.50 (d, J=1.9 Hz, 1H),7.17 (t, J=74.0 Hz, 1H), 7.16 (s, 1H), 6.35 (br s, 2H), 4.62-4.50 (m,2H), 4.45-4.32 (m, 2H), 3.82-3.70 (m, 1H), 3.70-3.60 (m, 3H), 3.28-3.23(m, 2H), 2.17-2.03 (m, 1H), 1.05-0.85 (m, 4H).

Example 2

The compounds disclosed in Table 1 were prepared following the syntheticsteps described in general Methods A-J as described above in Example 1with modifying the starting reactants and/or intermediates and in thosemethods as would be known to one skilled in the art in view of the finalcompound structures to arrive at the compounds in Table 1. The compoundsdisclosed in Table 1 were tested for DLK inhibitory activity asdescribed in Example 3.

TABLE 1 DLK Ki MS No (μM) Structure ¹H NMR [MH]⁺ Method 1 6.43

1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 21.2 Hz, 1H), 7.66 (s, 2H),7.58-7.40 (m, 6H), 4.12-3.89 (m, 1H), 3.80-3.52 (m, 4H), 3.17 (d, J =4.7 Hz, 1H), 2.66-2.56 (m, 3H), 2.41-2.04 (m, 2H). 429 H 2 1.7

1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 2H), 7.79-7.59 (m, 1H), 7.50-7.41(m, 3H), 7.41-7.36 (m, 2H), 7.24 (s, 2H), 7.12- 6.91 (m, 1H), 4.62- 4.44(m, 1H), 3.76- 3.53 (m, 1H), 3.19- 2.80 (m, 3H), 2.64- 2.59 (m, 2H),2.10- 2.02 (m, 1H), 1.89- 1.47 (m, 3H). 375 H 3 6.43

1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.66 (s, 2H), 7.46- 7.42 (m,3H), 7.42- 7.36 (m, 2H), 7.01 (s, 1H), 4.65-4.37 (m, 1H), 4.08 (q, J =5.3 Hz, 1H), 3.77-3.51 (m, 1H), 3.17 (d, J = 5.3 Hz, 2H), 3.14-2.89 (m,3H), 2.10-2.02 (m, 1H), 1.91-1.50 (m, 3H). 443 H 4 1.73

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 9.00 (s, 1H), 7.83- 7.68 (m,1H), 7.58- 7.50 (m, 2H), 7.51- 7.39 (m, 3H), 7.28- 7.22 (m, 2H), 4.00-3.43 (m, 4H), 2.65- 2.55 (m, 3H), 2.42- 2.06 (m, 2H). 361 H 5 0.83

390 I 6 0.001

1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.98 (s, 1H), 7.17 (t, J =73.9 Hz, 1H), 6.45 (s, 2H), 5.01 (s, 1H), 4.68 (s, 1H), 3.91 (t, 2H),3.81-3.69 (m, 3H), 3.66 (d, J = 7.4 Hz, 1H), 3.47 (d, J= 10.6, 1.5 Hz,1H), 3.40-3.23 (m, 1H), 2.46 (q, J = 7.4, 6.9 Hz, 1H), 1.87 (s, 2H). 441E 7 0.10

1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.00 (s, 2H), 4.98 (s, 1H),4.67 (s, 1H), 4.08 (t, J= 12.1 Hz, 2H), 3.88-3.71 (m, 3H), 3.65 (d, J =7.4 Hz, 1H), 3.47 (d, J= 10.3 Hz, 1H), 3.37 (s, 1H), 2.17-1.95 (m, 2H),1.88 (s, 2H), 1.78-1.58 (m, 2H). 390 E 8 0.22

1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s,2H), 5.11- 4.74 (m,2H), 4.67 (s, 1H), 3.98 (s, 2H), 3.78 (d, J = 7.0 Hz, 1H), 3.73- 3.55(m, 3H), 3.45 (d, 1H), 2.00-1.76 (m, 4H), 1.76-1.58 (m, 2H). 372 E 90.11

¹H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 2H), 6.68 (s, 1H), 5.34(s,2H), 4.97-4.95 (m, 1H), 4.69-4.62 (m, 4H), 3.83-3.78 (m, 1H), 3.55(s, 2H), 3.14 (d, J = 8.8 Hz, 2H), 2.94- 2.93 (m, 1H), 2.50 (d, J = 8.4Hz, 2H), 2.35- 2.33 (m, 1H), 2.13 (s, 2H), 1.99 (s, 2H), 1.46- 1.44 (m,2H). 392.2 C 10 0.01

¹H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.01 (s, 1H), 7.64 (s, 1H),7.21 (t, J = 73.6 Hz, 1H), 6.72 (s, 2H), 3.78-3.73 (m, 2H), 3.65-3.60(m, 1H), 3.40-3.35 (m, 1H), 2.27-2.16 (m, 5H), 1.85 (t, J = 3.2 Hz, 1H),1.00-0.93 (m, 7H). 416.1 C 11 0.01

¹H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.01 (s, 1H), 7.64 (s, 1H),7.21 (t, J = 73.6 Hz, 1H), 6.72 (s, 2H), 3.76-3.73 (m, 2H), 3.69-3.68(m, 1H), 3.39-3.36 (m, 1H), 2.26-2.24 (m, 1H), 2.18-2.17 (m, 1H),2.11-2.10 (m, 1H), 1.94 (s, 3H), 1.86 (t, J = 3.2 Hz, 1H), 1.00-0.97 (m,4H). 402.1 C 12 0.01

¹H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.36 (s, 1H), 6.79 (s, 2H),6.53-6.21 (m, 1H), 5.10-4.89 (m, 1H), 4.80-4.78 (m, 1H), 4.74-4.63 (m,1H), 3.55-3.51 (m, 1H), 3.44-3.35 (m, 2H), 3.23-2.84 (m, 4H), 2.82 (s,1H), 2.00 (s, 1H), 1.91 (s, 3H), 1.83-1.81 (m, 2H), 1.29 (d, J = 2.0 Hz,2H). 459.9 B 13 0.20

¹H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.02 (s, 1H), 6.72 (s,1H), 6.58 (t, J = 73.6 Hz, 1H), 4.97- 4.94 (m, 3H), 3.56 (s, 2H), 3.28(d, J = 8.4 Hz, 2H), 3.15-3.08 (m, 2H), 2.95-2.93 (m, 1H), 2.78 (d, J =8.4 Hz, 2H), 2.25 (d, J = 2.8 Hz, 1H), 2.12 (s, 2H), 1.99 (s, 2H),1.49-1.43 (m, 2H). 483.14 C 14 0.43

¹H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 2H), 7.09 (s, 2H), 7.03 (s, 1H),4.83 (br.s, 1H), 3.43 (s, 2H), 3.26-3.24 (m, 2H), 3.13 (d, J = 8.8 Hz,2H), 2.89-2.87 (m, 1H), 2.74-2.72 (m, 2H), 2.12-2.11 (m, 1H), 2.03 (s,2H), 1.93 (s, 2H), 1.30-1.29 (m, 2H). 418.1 C 15 0.001

¹H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.16 (s, 1H), 7.04 (s, 1H),6.91 (s, 2H), 4.84-4.82 (m, 1H), 4.05 (s, 1H), 3.45 (s, 3H), 3.19 (d, J= 8.8 Hz, 2H), 2.91-2.89 (m, 1H), 2.35 (s, 2H), 2.26 (s, 1H), 1.98-1.95(m, 4H), 1.33-1.32 (m, 2H), 1.08 (s, 6H). 491.2 C 16 0.001

¹H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.39 (s, 1H), 7.06 (s, 1H),6.91 (s, 2H), 4.83-4.81 (m, 1H), 4.02 (s, 1H), 3.42 (s, 2H), 3.16-3.14(m, 2H), 2.87-2.85 (m, 1H), 2.48 (s, 2H), 2.31 (s, 2H), 2.23 (s, 1H),1.95-1.92 (m, 4H), 1.29 (d, J = 2.8 Hz, 2H), 1.05 (s, 6H). 475.0 C 170.001

¹H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.02 (s, 1H), 6.68 (s,1H), 6.58 (t, J = 73.6 Hz, 1H), 4.98 (s, 3H), 3.56 (s, 2H), 3.31- 3.28(m, 2H), 3.01- 2.94 (m, 2H), 2.75 (d, J = 8.4 Hz, 2H), 2.50 (s, 2H),2.26 (s, 1H), 2.10 (s, 2H), 1.99 (s, 2H), 1.80-1.70 (m, 2H), 1.19 (s,6H). 473.17 C 18 0.05

¹H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.13 (s, 1H), 7.07 (s, 1H),6.94 (s, 2H), 4.85-4.83 (m, 1H), 3.74-3.65 (m, 3H), 3.45-3.40 (m, 3H),2.95-2.91 (m, 1H), 2.23-2.17 (m, 2H), 1.96-1.93 (m, 4H), 1.74 (s, 1H),1.33 (s, 2H), 1.30-1.22 (m, 1H). 460.9 C 19 0.03

¹H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.37 (s, 1H), 7.09 (s, 1H),6.94 (s, 2H), 4.84-4.82 (m, 1H), 3.71-3.64 (m, 3H), 3.43-3.35 (m, 2H),3.34-3.31 (m, 1H), 3.26-3.21 (m, 1H), 2.89-2.87 (m, 1H), 2.21-2.14 (m,2H), 1.94-1.90 (m, 4H), 1.73-1.71 (m, 1H), 1.31 (d, J = 4.0 Hz, 2H).445.0 C 20 0.01

¹H NMR (400 MHz, Methanol-d4) δ 8.62 (s, 1H), 8.17 (s, 1H), 6.85 (s,1H), 3.80-3.70 (m, 1H), 3.54-3.50 (m, 3H), 3.38 (s, 3H), 3.20 (d, J =9.6 Hz, 2H), 2.95- 2.90 (m, 1H), 2.71- 2.69 (m, 2H), 2.58- 2.55 (m, 2H),2.29 (s, 1H), 2.09-2.04 (m, 3H), 1.42-1.41 (m, 1H), 1.29 (s, 3H). 477.14C 21 0.007

¹H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.38 (s, 1H), 7.09 (s, 1H),6.91 (s, 2H), 4.82-4.81 (m, 1H), 3.42-3.37 (m, 8H), 3.36-3.34 (m, 2H),3.21 (s, 2H), 3.06 (d, J = 9.2 Hz, 1H), 2.87-2.84 (m, 1H), 2.58-2.57 (m,1H), 2.39 (d, J = 8.8 Hz, 1H), 2.20 (s, 1H), 1.97- 1.93 (m, 3H), 1.29(d, J = 2.4 Hz, 1H). 461.0 C 22 0.03

¹H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 2H), 6.66 (s, 1H), 5.21 (s,2H), 4.96 (d, J = 6.8 Hz, 1H), 3.54 (s, 2H), 3.50-3.47 (m, 2H), 3.38 (s,3H), 3.22 (d, J = 8.8 Hz, 2H), 2.96- 2.94 (m, 1H), 2.72- 2.69 (m, 2H),2.51 (d, J = 8.4 Hz, 2H), 2.35- 2.32 (m, 1H), 2.09 (s, 2H), 1.99 (s,2H), 1.46- 1.44 (m, 2H). 393.9 C 23 0.02

¹H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H), 8.10 (s, 1H), 6.52 (br.s,1H), 5.08 (br.s, 1H), 4.71 (s, 1H), 3.86 (d, J = 6.8 Hz, 1H), 3.78 (d, J= 7.2 Hz, 1H), 3.52 (d, J = 10.0 Hz, 1H), 3.35-3.31 (m, 1H), 2.06-2.02(m, 1H), 2.01-1.96 (m, 2H), 1.08-1.05 (m, 2H), 0.95-0.92 (m, 2H). 394.19A 24 1.61

1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 6.98 (s, 2H), 4.96 (s, 1H),4.66 (s, 1H), 4.30-4.22 (m, 1H), 4.21-4.13 (m, 2H), 3.86-3.73 (m, 3H),3.71-3.61 (m, 2H), 3.43 (d, J = 10.4, 2.5 Hz, 1H), 3.24 (s, 3H), 1.89(s, 2H). 355 E 25 1.09

1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 6.98 (s, 2H), 4.95 (s, 1H),4.66 (s, 1H), 3.76 (d, J = 7.2, 1.5 Hz, 1H), 3.68 (s, 3H), 3.64 (d, J =7.2 Hz, 1H), 3.43 (d, J = 10.5, 1.4 Hz, 1H), 1.85 (s, 2H), 1.26 (s, 5H).353 E 26 0.01

¹H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.86 (s, 1H), 6.92 (t, J =72.0 Hz, 1H), 6.24 (br.s, 1H), 4.96- 4.90 (m, 3H), 4.79- 4.74 (m, 2H),4.55 (s, 2H), 4.10 (s, 1H), 3.81 (s, 1H), 3.62 (s, 2H), 3.55-3.52 (m,1H), 3.04-2.97 (m, 3H), 2.11-2.06 (m, 3H), 1.96-1.94 (m, 1H), 1.51-1.44(m, 2H). 472.0 B 27 0.001

¹H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.97 (s, 1H), 7.12 (t, J =74.0 Hz, 1H), 6.27 (s, 1H), 6.10 (s, 2H), 5.30 (br.s, 1H), 4.97 (s, 1H),4.86 (d, J= 7.2 Hz, 1H), 3.65-3.57 (m, 2H), 3.48 (s, 3H), 3.44-3.42 (m,1H), 3.16-3.11 (m, 3H), 2.91-2.89 (m, 1H), 1.95-1.88 (m, 4H), 1.34-1.20(m, 8H). 516.0 B 28 0.001

¹H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.97 (s, 1H), 7.18 (t, J =73.6 Hz, 1H), 6.47 (s, 2H), 6.16 (br.s, 1H), 4.99 (br.s, 1H), 4.84-4.70(m, 2H), 4.13-4.09 (m, 1H), 3.92-3.91 (m, 1H), 3.56-3.50 (m, 5H),3.30-3.24 (m, 5H), 2.90-2.88 (m, 1H), 1.94-1.85 (m, 3H), 1.31-1.20 (m,2H). 488.0 B 29 0.005

1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.99 (s, 1H), 7.39- 6.96 (m,1H), 6.66- 6.12 (m, 3H), 5.51- 5.39 (m, 1H), 5.38- 5.26 (m, 1H), 5.01(s, 1H), 4.68 (s, 1H), 4.02- 3.84 (m, 2H), 3.79 (d, J = 7.2, 1.6 Hz,1H), 3.75 -3.56 (m, 3H), 3.47 (d, J = 10.4, 1.4 Hz, 1H), 3.37 (s, 1H),1.87 (s, 2H). 441 E 30 0.81

¹H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.13 (s, 2H), 7.11 (s, 1H), 4.93(d, J = 7.0 Hz, 1H), 3.51 (s, 2H), 2.98- 2.91 (m, 3H), 2.76 (t, J = 2.8Hz, 1H), 2.01 (d, J = 16.4 Hz, 4H), 1.47 (dd, J = 3.9, 1.7 Hz, 2H), 1.36(dd, J = 4.3, 1.7 Hz, 2H), 1.24 (s, 1H). 336 C 31 0.03

1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.94 (s, 1H), 7.35- 6.93 (m,1H), 6.43 (s, 2H), 4.96 (s, 1H), 4.66 (s, 1H), 3.99 (t, J = 7.4 Hz, 4H),3.77 (d, J = 7.5, 1.5 Hz, 1H), 3.64 (d, J = 7.4 Hz, 1H), 3.44 (d, J =10.0 Hz, 1H), 2.31-2.18 (m, 2H), 1.85 (s, 2H). 391 E 32 0.02

1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.95 (s, 1H), 7.36- 6.95 (m,1H), 6.46 (s, 2H), 5.58-5.33 (m, 1H), 4.98 (s, 1H), 4.67 (s, 1H),4.40-4.26 (m, 2H), 4.06 (d, 1H), 4.00 (d, J = 11.1, 3.2 Hz, 1H), 3.78(d, J = 7.2, 1.5 Hz, 1H), 3.65 (d, J = 7.4 Hz, 1H), 3.45 (d, J = 10.4Hz, 1H), 1.86 (s, 2H). 409 E 33 1.07

1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 6.32 (s, 1H),4.97 (s, 2H), 4.69-4.59 (m, 2H), 3.82-3.74 (m, 2H), 3.67 (dd, J = 7.3,5.9 Hz, 2H), 3.45 (td, J = 8.6, 7.4, 4.3 Hz, 3H), 3.33 (d, J = 8.9 Hz,2H), 1.89-1.77 (m, 4H). 368 E 34 0.024

427 E 35 0.17

1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.10 (s, 2H), 6.99 (s, 1H), 4.91(d, J = 7.0 Hz, 1H), 3.50 (s, 2H), 3.15 (q, J = 10.2 Hz, 3H), 2.96-2.90(m, 1H), 2.88-2.80 (m, 1H), 2.01-1.88 (m, 6H), 1.72-1.65 (m, 2H),1.65-1.56 (m, 2H), 1.35 (dd, J = 4.3, 1.7 Hz, 2H). 446 C 36 0.22

¹H NMR (400 MHz, Methanol-d4) δ 8.85 (s, 2H), 6.07 (br.s, 1H), 4.87 (d,J = 6.8 Hz, 1H), 4.54 (br.s, 1H), 3.83 (s, 1H), 3.51 (s, 3H), 3.34- 3.30(m, 1H), 3.11- 3.08 (m, 1H), 2.89- 2.88 (m, 1H), 2.61- 2.50 (m, 2H),1.98- 1.92 (m, 4H), 1.38 (d, J = 4.0 Hz, 2H), 1.06 (dd, J = 6.0, 15.2Hz, 6H). 393.22 B 37 0.22

¹H NMR (400 MHz, Methanol-d4) δ 8.86 (s, 2H), 6.11 (br.s, 1H), 4.88 (d,J = 6.8 Hz, 1H), 4.60 (br.s, 1H), 3.70 (s, 4H), 3.40-3.31 (m, 1H),2.95-2.91 (m, 2H), 2.66-2.56 (m, 3H), 2.00-1.86 (m, 4H), 1.41-1.40 (m,2H), 1.10 (t, J = 3.2 Hz, 3H). 379.23 B 38 0.29

¹H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.95 (d, J = 6.4 Hz, 2H), 6.25(br.s, 1H), 4.83 (d, J = 7.6 Hz, 2H), 4.56 (t, J = 6.8 Hz, 2H), 4.35 (t,J = 6.0 Hz, 1H), 4.28 (t, J = 6.4 Hz, 1H), 3.90-3.88 (m, 1H), 3.60-3.50(m, 1H), 3.45 (s, 2H), 3.20-3.15 (m, 2H), 2.89-2.87 (m, 1H), 2.85-2.81(m, 1H), 2.68-2.66 (m, 1H), 1.93 (s, 2H), 1.84- 1.82 (m, 1H), 1.80- 1.75(m, 1H), 1.32- 1.15 (m, 2H). 407.2 B 39 0.07

¹H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 7.04 (s, 2H), 6.31 (s, 1H),5.49-5.34 (m, 2H), 4.85 (d, J = 6.4 Hz, 1H), 3.91-3.84 (m, 2H),3.69-3.61 (m, 2H), 3.47 (s, 2H), 2.90- 2.88 (m, 1H), 1.94 (s, 2H),1.32-1.23 (m, 2H). 359.8 B 40 0.004

¹H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.97 (s, 1H), 7.18 (t, J =74.0 Hz, 1H), 6.47 (s, 2H), 6.17 (br.s, 1H), 4.98 (br.s, 1H), 4.84-4.67(m, 2H), 3.56-3.54 (m, 1H), 3.50-3.38 (m, 4H), 3.33-3.26 (m, 2H), 2.88(d, J = 3.2 Hz, 1H), 2.03 (s, 1H), 1.94 (s, 3H), 1.87-1.84 (m, 2H),1.32-1.31 (m, 2H). 457.9 B 41 0.28

1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.11 (s, 2H), 7.02 (s, 1H), 4.89(d, J = 7.0 Hz, 1H), 4.57-4.50 (m, 1H), 4.31-4.21 (m, 1H), 3.48 (s, 2H),3.18- 3.09 (m, 1H), 2.95- 2.90 (m, 1H), 2.00 (s, 3H), 2.00-1.94 (m, 3H),1.91-1.70 (m, 7H), 1.34 (dd, J = 4.4, 1.8 Hz, 2H). 406 C 42 0.17

1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 5.91- 5.77 (m,1H), 5.18- 5.08 (m, 2H), 4.96 (s, 1H), 4.67 (s, 1H), 4.53- 4.44 (m, 2H),3.77 (d, J = 7.2, 1.5 Hz, 1H), 3.41- 3.32 (m, 1H), 3.65 (d, J = 7.3 Hz,1H), 3.45 (dd, J = 10.6, 1.5 Hz, 1H), 3.18 (t, J = 12.1 Hz, 2H), 2.43(d, J = 7.2 Hz, 1H), 2.37 (d, J = 7.4 Hz, 1H), 1.86 (s, 2H), 1.83-1.72(m, 2H), 1.72-1.51 (m, 2H). 412 E 43 1.61

1H NMR (400 MHz, DMSO-d6) δ 3.14- 2.98 (m, 1H), 2.82- 2.72 (m, 1H), 2.41(s, 1H), 2.13 (d, J = 3.4 Hz, 3H), 1.96 (d, J = 10.5 Hz, 1H), 1.86 (s,3H), 1.53 (d, J = 10.6 Hz, 1H), 3.38-3.31 (m, 1H), 8.89 (d, J = 10.6 Hz,2H), 6.94 (s, 2H), 5.02-4.88 (m, 1H), 4.66 (s, 1H), 4.47-4.27 (m, 1H),3.77 (d, J = 7.2 Hz, 1H), 3.66 (s, 1H), 3.55-3.39 (m, 3H). 395 E 44 0.07

1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 4.96 (s, 1H),4.67 (s, 1H), 3.87-3.72 (m, 5H), 3.41-3.32 (m, 1H), 3.66 (d, J = 7.2 Hz,1H), 3.46 (d, J = 10.5, 1.4 Hz, 1H), 2.31-2.17 (m, 2H), 2.10-1.96 (m,2H), 1.92-1.78 (m, 4H). 404 E 45 1.75

1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 6.97 (s, 2H), 4.96 (s, 1H),4.66 (s, 1H), 3.77 (d, J = 7.5, 1.4 Hz, 1H), 3.71 (t, J = 4.9 Hz, 4H),3.65 (d, J = 7.3 Hz, 1H), 3.44 (d, J = 10.5, 1.4 Hz, 1H), 3.33 (s, 1H),2.74-2.64 (m, 1H), 2.27 (t, J = 5.0 Hz, 4H), 1.97 (qd, J = 7.2, 3.1 Hz,2H), 1.92-1.72 (m, 4H), 1.72-1.54 (m, 2H). 409 E 46 1.61

1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 6.97 (s, 2H), 4.95 (s, 1H),4.66 (s, 1H), 3.76 (d, J = 7.2. 1.5 Hz, 1H), 3.68 (s, 4H), 3.64 (d, J =7.3 Hz, 1H), 3.43 (d, J = 10.5, 1.4 Hz, 1H), 2.24 (s, 4H), 2.13 (s, 3H),1.85 (s, 2H), 1.71 (t, J = 5.3 Hz, 4H). 409 E 47 0.07

1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 6.94 (s, 2H), 4.93 (s, 1H),4.66 (s, 1H), 3.77 (d, J = 7.2, 1.6 Hz, 1H), 3.66 (d, J = 7.2 Hz, 1H),3.63-3.51 (m, 4H), 3.45 (d, J = 10.5, 1.4 Hz, 1H), 1.87 (t, 2H), 1.14(t, 6H). 342 E 48 1.61

1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H),4.66 (s, 1H), 3.77 (d, J = 7.5, 1.5 Hz, 1H), 3.75-3.68 (m, 4H),3.41-3.32 (m, 1H), 3.65 (d, J = 7.3 Hz, 1H), 3.45 (d, J = 10.5, 1.4 Hz,1H), 3.17 (s, 1H), 2.34 (t, J = 5.0 Hz, 4H), 2.20 (s, 3H), 1.86 (s.2H).369 E 49 0.54

1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 6.96 (s, 2H), 4.95 (s, 1H),4.66 (s, 1H), 3.82-3.69 (m, 5H), 3.65 (d, J = 7.3 Hz, 1H), 3.49-3.41 (m,1H), 3.40-3.32 (m, 1H), 1.92-1.80 (m, 2H), 1.67-1.56 (m, 2H), 1.56-1.45(m, 4H). 354 E 50 0.41

1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 6.97 (s, 2H), 4.95 (s, 1H),4.66 (s, 1H), 3.99 (t, J = 7.5 Hz, 4H), 3.77 (dd, J = 7.3, 1.5 Hz, 1H),3.64 (d, J = 7.3 Hz, 1H), 3.43 (dd, J = 10.5, 1.5 Hz, 1H), 3.40- 3.32(m, 1H), 3.17 (s, 1H), 2.24 (p, J = 7.5 Hz, 2H), 1.85 (s, 2H). 326 E 510.20

1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 6.97 (s, 2H), 6.31 (s, 1H),4.97 (s, 1H), 4.66 (s, 1H), 3.84-3.69 (m, 3H), 3.65 (d, J = 7.3 Hz, 1H),3.51-3.41 (m, 3H), 2.89 (q, J = 9.3, 8.1 Hz, 2H), 2.48-2.31 (m, 2H),2.16-1.98 (m, 2H), 1.86 (s, 2H). 416 E 52 0.086

1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.95 (s, 2H), 6.27 (s, 1H),4.96 (s, 1H), 4.66 (s, 1H), 3.77 (d, J = 7.3, 1.5 Hz, 1H), 3.65 (d, J =7.3 Hz, 1H), 3.58- 3.41 (m, 5H), 1.96- 1.79 (m, 6H). 340 E 53 0.27

1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.03 (s, 2H), 6.35 (s, 1H),4.99 (s, 1H), 4.68 (s, 1H), 4.41 (t, J = 12.6 Hz, 4H), 3.78 (dd, J =7.5, 1.5 Hz, 1H), 3.66 (d, J = 7.4 Hz, 1H), 3.50-3.42 (m, 1H), 3.40-3.31(m, 1H), 1.87 (s, 2H). 362 E 54 0.16

1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 7.00 (s, 2H), 4.97 (s, 1H),4.67 (s, 1H), 4.19 (d, J = 9.3, 3.2 Hz, 2H), 3.94 (d,J = 9.2, 2.8 Hz,2H), 3.77 (d, J = 7.5, 1.5 Hz, 1H), 3.65 (d, J = 7.4 Hz, 1H), 3.44 (d, J= 10.5, 1.5 Hz, 1H), 2.11-1.99 (m, 2H), 1.86 (s, 2H). 402 E 55 0.13

1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H),4.67 (s, 1H), 3.84-3.58 (m, 5H), 3.49-3.41 (m, 2H), 3.04-2.90 (m, 2H),2.28-2.08 (m, 2H), 2.08-1.96 (m, 1H), 1.86 (s, 2H), 1.68-1.57 (m, 1H).416 E 56 1.61

1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 6.98 (s, 2H), 4.96 (s, 1H),4.66 (s, 1H), 4.08 (d, J = 9.0, 3.2 Hz, 2H), 3.82-3.71 (m, 3H), 3.65 (d,J = 7.2 Hz, 1H), 3.43 (d, J = 10.6, 1.5 Hz, 1H), 3.17 (d, J = 5.0 Hz,1H), 2.62 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H), 2.05-1.97 (m, 2H), 1.85 (s,2H), 1.73- 1.62 (m, 2H). 395 E 57 0.12

1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 6.96 (s, 2H), 4.95 (s, 1H),4.66 (s, 1H), 3.84-3.79 (m, 4H), 3.77 (d, J = 7.2, 1.4 Hz, 1H), 3.66 (d,J = 7.2 Hz, 1H), 3.45 (d, J = 10.5, 1.5 Hz, 1H), 1.86 (s, 2H), 1.41-1.28(m, 4H), 0.34 (s, 4H). 380 E 58 0.21

1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.09 (s, 2H), 6.99 (s, 1H), 4.92(d, J = 7.0 Hz, 1H), 4.58 (t, J = 6.2 Hz, 2H), 4.35 (t, J = 5.7 Hz, 2H),3.73-3.65 (m, 1H), 3.50 (s, 2H), 3.13 (s, 2H), 2.93 (dd, J = 6.8, 3.2Hz, 1H), 2.90- 2.79 (m, 1H), 2.02- 1.81 (m, 6H), 1.69- 1.57 (m, 4H),1.35 (dd, J = 4.3, 1.8 Hz, 2H) 420 C 59 0.02

¹H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 2H), 6.65 (s, 1H), 5.49(s,2H), 4.95 (d, J = 6.0 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.72 (s,2H), 3.54 (s, 3H), 2.95 (s, 1H), 2.30 (s, 2H), 2.06 (s, 3H), 2.00 (s,2H), 1.70 (s, 1H), 1.45 (s, 2H). 377.8 C 60 0.01

¹H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 6.40- 6.14 (m,1H), 4.83 (d, J = 6.8 Hz, 1H), 3.99 (s, 1H), 3.68-3.60 (m, 1H), 3.45(s,2H), 3.28- 3.27 (m, 2H), 3.04 (d, J = 7.6 Hz, 1H), 2.89- 2.87 (m,1H), 2.57- 2.54 (m, 1H), 2.45- 2.41 (m, 2H), 1.93- 1.91 (m, 2H), 1.82-1.71 (m, 2H), 1.32- 1.29 (m, 2H), 1.23- 1.15 (m, 1H), 1.04 (s, 6H).423.2 B 61 0.01

¹H NMR (400 MHz, Methanol-d4) δ 8.84 (s, 2H), 6.09 (br.s, 1H), 4.95-4.87(m, 2H), 4.67 (br.s, 1H), 3.71 (s, 1H), 3.62-3.52 (m, 4H), 3.48-3.45 (m,1H), 3.34-3.31 (m, 3H), 3.00-2.95 (m, 1H), 2.92-2.90 (m, 1H), 2.76-2 74(m, 2H), 2.67-2.64 (m, 1H), 1.98-1.94 (m, 3H), 1.88-1.82 (m, 1H),1.42-1.38 (m, 2H). 409.2 B 62 0.003

¹H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.96 (s, 1H), 7.17 (t, J =74.0 Hz, 1H), 6.44 (s, 2H), 6.30 (br.s, 1H), 4.96 (s, 1H), 4.66 (s, 1H),3.86-3.76 (m, 3H), 3.64 (d, J = 7.2 Hz, 1H), 3.45-3.40 (m, 4H), 1.85 (s,2H), 1.61- 1.58 (m, 2H), 0.71- 0.66 (m, 1H), 0.14- 0.11 (m, 1H). 416.8 A63 0.53

¹H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 2H), 1.17 (s, 1H), 5.32 (s,2H), 3.99 (d, J = 12.0 Hz, 1H), 3.74- 3.72 (m, 2H), 3.56 (dd, J = 4.0,12.4 Hz, 1H), 2.33-2.29 (m, 2H), 2.25-2.20 (m, 1H), 2.07 (s, 3H),1.80-1.78 (m, 1H), 1.13-1.11 (m, 2H), 1.04-1.02 (m, 2H). 336.9 C 64 0.27

¹H NMR (400 MHz, DMSO) δ 8.91 (s,2H), 6.92 (br s, 2H), 6.50 (s, 1H),5.03 (br s, 1H), 4.80 (d, J = 6.9 Hz, 1H), 4.36 (br s, 1H), 3.44 (s,2H), 2.85 (m, 1H), 2.18- 1.51 (m, 14H), 1.39- 1.27 (m, 2H). 378 I 650.04

1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 6.99 (s, 2H), 5.49- 5.38 (m,1H), 5.38- 5.26 (m, 1H), 5.00 (s, 1H), 4.68 (s, 1H), 3.44- 3.32 (m, 1H),4.03- 3.84 (m, 2H), 3.78 (d, J = 7.5, 1.5 Hz, 1H), 3.75- 3.57 (m, 3H),3.46 (d, J = 10.5, 1.6 Hz, 1H), 3.37 (s, 1H), 1.95- 1.80 (m, 2H). 376 E66 0.03

1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 6.99 (s, 2H), 5.00 (s, 1H),4.67 (s, 1H), 3.91 (t, J = 13.5 Hz, 2H), 3.80-3.68 (m, 3H), 3.65 (d, J =7.3 Hz, 1H), 3.46 (d, 1H), 3.37 (s, 1H), 1.87 (s, 2H). 376 E 67 0.65

1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 7.00 (s, 2H), 5.45 (d, J =57.9, 6.1, 3.2 Hz, 1H), 4.97 (s, 1H), 4.67 (s, 1H), 4.40-4.25 (m, 2H),,4.12-4.03 (m, 1H), 4.03-3.96 (m, 1H), 3.77 (d, J = 7.3, 1.5 Hz, 1H),3.65 (d, J = 7.3 Hz, 1H), 3.44 (d, J = 10.5, 1.5 Hz, 1H), 3.41- 3.31 (m,1H), 3.35 (s, 1H), 1.86 (s, 2H). 395 E 68 1.61

1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H),4.66 (s, 1H), 3.77 (d, J = 7.5, 1.7 Hz, 1H), 3.74-3.61 (m, 5H), 3.45 (d,J = 10.5, 1.5 Hz, 1H), 3.35 (s, 1H), 2.56 (t, J = 5.0 Hz, 4H), 1.86 (s,2H), 1.68- 1.59 (m, 1H), 0.43 (m, 2H), 0.36 (q, J = 3.2, 2.6 Hz, 2H).395 E 69 0.11

1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 2H),4.75 (s, 2H), 4.67 (s, 2H), 3.77 (d, J = 7.5, 1.7 Hz, 2H), 3.66 (d, J =7.4 Hz, 2H), 3.64-3.50 (m, 1H),), 3.56 (t, J = 8.9 Hz, 1H), 3.50-3.40(d, 1H), 3.40- 3.35 (m, 3H), 3.45 (d, J = 9.9, 1.7 Hz, 1H), 2.93 (s,1H), 2.28-2.10 (m, 1H), 2.10-1.96 (m, 1H), 1.89 (d, J = 18.5 Hz, 4H).402 E 70 0.22

1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H),4.85 (d, J = 13.2 Hz, 2H), 4.67 (s, 1H), 3.78 (d, J = 7.3, 1.4 Hz, 1H),2.64-2.52 (m, 1H), 3.65 (d, J = 7.4 Hz, 1H), 3.46 (d, J = 10.5, 1.4 Hz,1H), 3.35 (s, 1H), 2.82 (t, J = 12.8 Hz, 2H), 1.86 (d, J = 11.0 Hz, 4H),1.45- 1.28 (m, 2H). 422 E 71 0.09

¹H NMR (400 MHz, DMSO) δ 8.92 (s, 2H), 7.10 (d, J = 1.1 Hz, 1H), 6.91(br s, 2H), 6.46 (d, J = 1.1 Hz, 1H), 4.88 (d, J = 6.8 Hz, 1H), 3.44 (s,2H), 3.01-2.90 (m, 1H), 2.75-2.64 (m, 4H), 2.39-2.18 (m, 1H), 2.11-1.92(m, 3H), 1.41-1.27 (m, 2H). 333 G 72 0.04

¹H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.05 (s, 1H), 7.23 (t, J = 74.0Hz, 2H), 7.20 (s, 1H), 6.70 (br s, 2H), 4.95 (m, 1H), 3.54 (s, 2H),2.99-2.91 (m, 1H), 2.81 (m, 2H), 2.72- 2.60 (m, 2H), 2.32- 2.18 (m, 1H),2.13 1.94 (m, 3H), 1.45 1.38 (m, 2H). 399 I 73 0.002

¹H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.78 (s, 1H), 6.72 (t, J =73.6 Hz, 1H), 5.90 (s, 1H), 4.73-4.68 (m, 1H), 3.62 (br.s, 2H), 3.37 (s,2H), 3.30 (d, J = 10.4 Hz, 2H), 2.75- 2.73 (m, 1H), 1.83 (s, 2H),1.51-1.50 (m, 2H), 1.24-1.22 (m, 2H), 0.64-0.61 (m, 1H), 0.02-0.01 (m,1H). 401.0 A 74 0.05

¹H NMR (400 MHz, Chloroform-d) δ 8.54 (s, 1H), 7.91 (s, 1H), 5.92 (s,1H), 4.96 (d, J = 6.8 Hz, 2H), 4.89 (s, 2H), 4.70 (s, 1H), 3.92- 3.87(m, 2H), 3.58 (s, 2H), 3.52-4.94 (m, 2H), 2.92-2.90 (m, 1H), 1.96-1.93(m, 4H), 1.68-1.66 (m, 1H), 1.48-1.46 (m, 2H), 0.96-0.94 (m, 2H),0.69-0.67 (m, 2H). 390.9 A 75 0.009

¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.23 (s, 1H), 6.21 (br.s, 2H),5.92 (s, 2H), 4.96 (s, 1H), 4.80 (d, J = 7.2 Hz, 1H), 4.67-4.61 (m, 2H),3.75 (d, J = 6.4 Hz, 1H), 3.63 (d, J = 7.2 Hz, 1H), 3.43-3.42 (m, 4H),2.87-2.85 (m, 1H), 1.91-1.83 (m, 4H), 1.32-1.21 (m, 8H). 409.2 A 760.008

¹H NMR (400 MHz, Chloroform-d) δ 8.51 (s, 1H), 7.99 (s, 1H), 6.58 (t, J= 73.2 Hz, 1H), 6.29 (s, 1H), 5.12 (br.s, 1H), 4.91 (s, 2H), 4.74 (s,1H), 3.91-3.87 (m, 2H), 3.51-3.44 (m, 2H), 2.12-2.05 (m, 1H), 2.00-1.92(m, 2H), 1.15-1.07 (m, 2H), 0.97-0.95 (m, 2H). ¹H NMR (400 MHz, DMSO-d6)8 8.63 (s, 1H), 7.99 (s, 1H), 7.18 (t, 7 = 74.0 Hz, 1H), 6.80 (br.s,1H), 6.54 (s, 2H), 5.02 (s, 1H), 4.69 (s, 1H), 3.78 (d, J = 6.8 376.1376.1 A Hz, 1H), 3.64 (d, J = 7.2 Hz, 1H), 3.48-3.45 (m, 2H), 1.99-1.88(m, 3H), 0.99-0.88 (m, 4H). 77 0.16

1H NMR (400 MHz, DM SO) δ 8.94 (s, 2H), 8.40 (s, 1H), 7.12 (s, 2H), 7.03(s, 1H), 4.93 (d, J = 7.1 Hz, 1H), 3.81 (s, 2H), 3.04-2.94 (m, 2H),2.95-2.90 (m, 1H), 2.03-1.95 (m, 4H), 1.94-1.76 (m, 7H), 1.35 (dd, J =4.4, 1.7 Hz, 2H). 364 C 78 1.61

1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 2H), 7.00 (s, 2H), 4.98 (s, 1H),4.68 (s, 1H), 3.78 (d, J = 6.7 Hz, 1H), 3.65 (d, J = 7.4 Hz, 1H), 3.46(d, J = 10.1 Hz, 1H), 3.10-2.52 (m, 4H), 1.87 (s, 2H), 0.96 (s, 1H),0.55 (d, J = 7.5 Hz, 2H), 0.21 (s, 2H), 3.10- 2.52 (m, 4H). 409 E 790.06

¹H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.15 (t, 7 =74.0 Hz, 1H), 6.42 (s, 1H), 6.21 (s, 2H), 5.54 (s, 1H), 4.76- 4.74 (m,2H), 4.62 (s, 1H), 3.73 (d, J = 6.8 Hz, 1H), 3.63 (d, J = 7.6 Hz, 1H),3.45 (d, J = 8.8 Hz, 1H), 3.33 (s, 2H), 3.10 (d, J = 10.4 Hz, 1H),2.88-2.86 (m, 1H), 1.88-1.81 (m, 4H), 1.27-1.26 (m, 2H). 416.1 D 80 0.08

¹H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 6.99 (s, 2H), 6.38 (br.s, 1H),4.97-4.91 (m, 2H), 4.62 (s, 1H), 3.78 (d, J = 6.4 Hz, 1H), 3.67 (d, J =7.2 Hz, 1H), 3.47-3.41 (m, 4H), 2.96-2.90 (m, 1H), 1.98 (s, 2H),1.87-1.79 (m, 2H), 1.33 (d, J = 2.8 Hz, 2H). 351.8 B 81 0.038

¹H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 7.00 (s, 2H), 6.54- 6.10(br.s, 1H), 5.08- 4.96 (br.s, 1H), 4.66- 4.62 (m, 1H), 3.84- 3.81 (m,2H), 3.77- 3.75 (m, 1H), 3.63 (d, J = 7.2 Hz, 1H), 3.44- 3.39 (m, 4H),1.85 (s, 2H), 1.60-1.58 (m, 2H), 0.73-0.66 (m, 1H), 0.14-0.12 (m, 1H).352.19 B 82 0.034

¹H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.00 (s, 2H), 6.68- 6.12(br.s, 1H), 5.11- 4.95 (br.s, 1H), 4.88- 4.65 (m, 2H), 3.55- 3.33 (m,5H), 3.28- 3.23 (m, 1H), 2.88 (d, J = 6.8 Hz, 1H), 2.02 (s, 2H), 1.93(s, 3H), 1.86- 1.83 (m, 2H), 1.31 (s, 2H). 393.15 B 83 0.17

¹H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 2H), 5.92 (s, 1H), 5.22 (s,3H), 5.00-4.93 (m, 1H), 4.15-4.12 (m, 1H), 3.80 (s, 1H), 3.75- 3.72 (m,1H), 3.55 (s, 2H), 3.45-3.41 (m, 1H), 3.21-3.18 (m, 1H), 2.95-2.93 (m,1H), 2.74-2.71 (m, 1H), 2.50-2.47 (m, 1H), 2.00 (s, 2H), 1.47 (d, J =4.0 Hz, 2H). 399.8 B 84 0.051

¹H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.00 (s, 2H), 6.50- 6.15 (m,1H), 4.83 (d, J = 6.8 Hz, 1H), 3.69 (s, 1H), 3.51-3.48 (m, 3H),3.45-3.40 (m, 2H), 3.08-3.05 (m, 1H), 2.89-2.88 (m, 1H), 2.68-2.64 (m,1H), 2.02 (s, 1H), 1.87- 1.86 (m, 1H), 1.82- 1.77 (m, 1H), 1.38 (s, 3H),1.33-1.32 (m, 2H). 433.1 A 85 0.05

¹H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 6.94 (s, 2 H), 6.39 (s, 1H),4.78-4.76 (m, 1H), 4.54 (br.s, 2H), 2.84-2.83 (m, 1H), 2.46 (s, 2 H),1.88 (s, 4H), 1.75-1.67 (m, 5H), 1.42-1.27 (m, 5H). 363.9 A 86 0.21

¹H NMR (400 MHz, DMSO) δ 9.01 (s, 2H), 7.21 (br s, 2H), 7.20 (s, 1H),5.06-4.80 (m, 1H), 3.54 (s, 2H), 2.99- 2.89 (m, 1H), 2.85- 2.73 (m, 2H),2.70- 2.59 (m, 2H), 2.34- 2.14 (m, 1H), 2.14- 1.90 (m, 3H), 1.45- 1.33(m, 2H). 334 I 87 0.21

370 B 88 0.41

1H NMR (400 MHz, DMSO) δ 8.96 (s, 2H), 7.14-7.02 (m, 3H), 4.90 (d, J =6.0 Hz, 1H), 4.49 (dt, J = 19.6, 6.2 Hz, 4H), 3.57-3.45 (m, 3H),2.97-2.87 (m, 1H), 2.76-2.66 (m, 4H), 2.62 (s, 1H), 2.10- 2.03 (m, 2H),1.98 (s, 2H), 1.62 (s, 4H), 1.40- 1.33 (m, 2H). 420 C 89 0.01

¹H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.14 (s, 1H), 6.80 (s, 2H),6.23 (br.s, 1H), 5.00 (br.s, 1H), 4.82 (d, J =6.8 Hz, 1H), 4.67 (s, 1H),3.77 (d, J = 6.4 Hz, 1H), 3.65 (d, J = 7.2 Hz, 1H), 3.47-3.45 (m, 4H),2.90-2.88 (m, 1H), 1.94-1.86 (m, 4H), 1.32-1.31 (m, 2H). 434.9 A 90 0.13

¹H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 6.43- 6.09 (m,1H), 4.90- 4.65 (m, 2H), 3.69- 3.61 (m, 1H), 3.50- 3.39 (m, 5H), 2.88(d, J = 8.0 Hz, 2H), 2.79- 2.76 (m, 1H), 1.93 (s, 2H), 1.73-1.64 (m,2H), 1.31-1.28 (m, 2H). 351.18 B 91 0.1

1H NMR (400 MHz, DM SO) δ 8.95 (s, 2H), 7.08 (s, 2H), 7.01 (s, 1H), 4.89(d, J = 6.7 Hz, 1H), 3.49 (s, 2H), 2.96- 2.90 (m, 1H), 2.81- 2.68 (m,5H), 2.55 (s, 2H), 1.97 (d, J = 1.2 Hz, 2H), 1.68-1.51 (m, 4H), 1.35(dd, J = 4.3, 1.8 Hz, 2H) 364 C 92 0.002

1H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 7.95 (s, 1H), 7.18 (t, J = 73.9Hz, 1H), 6.38 (br s, 2H), 6.36-6.00 (m, 1H), 4.82 (d, J = 7.0 Hz, 1H),4.77-4.45 (m, 1H), 3.45 (s, 2H), 3.42- 3.34 (m, 1H), 3.16- 3.04 (m, 1H),2.88 (dd, J = 6.9, 3.1 Hz, 1H), 2.61 (s, 1H), 1.93 (s, 2H), 1.73-1.44(m, 5H), 1.41-1.26 (m, 3H). 415 E 93 0.01

1H NMR (400 MHz, DMSO) δ 8.88 (s, 2H), 6.93 (s, 2H), 6.35-6.10 (m, 1H),4.82 (d, J = 7.0 Hz, 1H), 4.77-4.42 (m, 1H), 3.44 (s, 2H), 3.37 (d, J =8.4 Hz, 1H), 3.21- 2.98 (m, 1H), 2.91- 2.83 (m, 1H), 2.61 (d, J = 1.9Hz, 1H), 1.92 (s, 2H), 1.72-1.52 (m, 4H), 1.51-1.43 (m, 1H), 1.36 (t, J= 8.6 Hz, 1H), 1.31 (dd, J = 4.3, 1.6 Hz, 2H). 350 E 94 0.028

¹H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 6.97 (s, 2H), 6.19 (s, 1H),4.82 (d, J = 6.4 Hz, 1H),3.74 (br.s, 2H), 3.44-3.38 (m, 4H), 2.88-2.87(m, 1H), 1.92-1.87 (m, 2H), 1.65 (s, 2H), 1.31 (s, 2H), 0.73-0.72 (m,1H), 0.13-0.12 (m, 1H). 335.8 A 95 0.68

¹H NMR (400 MHz, Methanol-d4) δ 8.76 (s, 2H), 6.45 (br.s, 1H), 5.02-4.98(m, 1H), 4.63 (s, 1H), 3.78-3.77 (m, 1H), 3.70-3.68 (m, 1H), 3.43-3.42(m, 1H), 3.38-3.30 (m, 1H), 1.98-1.97 (m, 1H), 1.88-1.85 (m, 2H),1.18-0.97 (m, 2H), 0.86-0.83 (m, 2H). 311.19 A 96 0.14

¹H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 6.41 (s, 1H),4.81-4.79 (m, 1H), 4.70-4.44 (m, 2H), 3.43 (s, 2H), 2.70- 2.69 (m, 2H),2.25- 2.24 (m, 2H), 1.92 (s, 2H), 1.80-1.73 (m, 4H), 1.64-1.61 (m, 2H),1.31-1.30 (m, 2H), 0.95 (s, 3H). 394.2 A 97 0.32

¹H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 2H), 6.08 (s, 1H), 5.70 (s,2H), 4.94 (d, J = 7.2 Hz, 1H), 4.21 (d, J = 12.8 Hz, 2H), 3.72- 3.64 (m,2H), 3.57 (s, 2H), 2.94-2.91 (m, 1H), 2.62-2.56 (m, 2H), 1.98 (d, J =2.0 Hz, 2H), 1.47 (dd, J = 2.0, 4.4 Hz, 2H), 1.28 (d, J = 6.8 Hz, 6H).368.0 A 98 0.101

¹H NMR (400 MHz, Methanol-d4) δ 8.85 (s, 2H), 6.30 (s, 1H), 4.88- 4.86(m, 1H), 4.44- 4.43 (m, 2H), 4.12- 4.06 (m, 2H), 3.53 (s, 2H), 3.10 (dd,J = 2.0, 12.8 Hz, 2H), 2.92- 2.90 (m, 1H), 2.00 (s, 1H), 1.95-1.91 (m,2H), 1.87-1.79 (m, 3H), 1.40 (dd, J = 2.0, 4.4 Hz, 2H). 365.9 A 99 0.043

¹H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2 H), 6.34 (s, 1H),4.84-4.82 (m, 2H), 3.40 (s, 4H), 2.96- 2.86 (m, 2H), 1.95 (d, J = 19.6Hz, 4 H), 1.32- 1.31 (m, 4H). 336.1 A 100 0.001

¹H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.97 (s, 1H), 7.18 (t, J =73.6 Hz, 1H), 6.47 (s, 2H), 6.25 (br.s, 1H), 5.00-4.97 (m, 1H),4.85-4.83 (m, 1H), 4.68 (s, 1H), 3.78 (d, J = 6.4 Hz, 1H), 3.66 (d, J =7.2 Hz, 1H), 3.52- 3.46 (m, 4H), 2.90- 2.89 (m, 1H), 1.95- 1.87 (m, 4H),1.32 (s, 2H). 416.9 A 101 0.026

¹H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.54 (s, 1H), 7.26 (br.s, 2H),6.50 (br.s, 1H), 5.04-5.01 (m, 1H), 4.86 (s, 1H), 4.68 (s, 1H), 3.78 (d,J = 7.2 Hz, 1H), 3.66 (d, J = 7.2 Hz, 1H), 3.47-3.44 (m, 4H), 2.92-2.89(m, 1H), 1.95-1.87 (m, 4H), 1.35-1.33 (m, 2H). 375.9 A 102 0.024

¹H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.23 (s, 1H), 6.66 (s, 2H),6.30-6.20 (m, 1H), 5.04-4.98 (m, 1H), 4.93-4.83 (m, 1H), 4.71-4.67 (m,1H), 3.77 (d, J = 6.0 Hz, 1H), 3.66 (d, J = 7.2 Hz, 1H), 3.52-3.44 (m,4H), 2.90-2.88 (m, 1H), 1.94-1.91 (m, 2H), 1.90-1.86 (m, 2H), 1.33-1.31(m, 2H). 385.0 A 103 0.018

¹H NMR (400 MHz, DMSO + H₂O-d6) δ 8.76- 8.75 (m, 1H), 8.32- 8.28 (m,1H), 6.60- 6.10 (m, 1H), 5.20- 5.00 (m, 1H), 4.90- 4.88 (m, 1H), 4.69-4.70 (m, 1H), 3.79- 3.77 (m, 2H), 3.51- 3.48 (m, 4H), 2.93- 2.91 (m,1H), 2.02- 1.99 (m, 2H), 1.95- 1.89 (m, 2H), 1.35 (s, 2H). 419.0 A 1040.069

¹H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 6.42 (s, 1H),4.82-4.80 (m, 1H), 4.59-4.54 (m, 4H), 3.90-3.86 (m, 1H), 2.89-2.87 (m,1H), 2.26-2.25 (m, 2H), 1.99-1.86 (m, 7H), 1.65-1.61 (m, 2H), 1.32-1.30(m, 2H). 380.1 A 105 1.36

1H NMR (400 MHz, DMSO) δ 8.86 (s, 2H), 6.75 (s, 2H), 6.61 (d, J = 1.7Hz, 1H), 5.81 (d, J = 1.7 Hz, 1H), 4.82-4.72 (m, 1H), 4.35 (s, 2H), 3.68(d, J = 10.8 Hz, 2H), 3.44 (d, J = 10.9 Hz, 2H), 3.37 (s, 2H), 2.95-2.87(m, 1H), 1.97-1.91 (m, 6H), 1.30 (dd, J = 4.3, 1.8 Hz, 2H). 365 D 1060.98

1H NMR (400 MH/. DMSO) δ 8.84 (s, 2H), 6.73 (s, 2H), 6.49 (d, J = 1.6Hz, 1H), 5.67 (d, J = 1.6 Hz, 1H), 4.77 (dd, J = 5.4, 1.6 Hz, 1H), 4.63(d, J = 6.8 Hz, 1H), 3.36 (s, 2H), 2.96-2.88 (m, 2H), 1.92 (dd, J =16.5, 1.6 Hz, 4H), 1.35-1.25 (m, 4H). 335 D 107 0.13

¹H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 2H), 7.00 (s, 2H), 6.52 (s, 1H),4.82 (d, J = 6.8 Hz, 1H), 4.65-4.50 (m, 2H), 3.62 (d, J = 10.8 Hz, 4H),3.53 (d, J = 10.4 Hz, 2H), 2.89- 2.87 (m, 1H), 1.96- 1.86 (m, 6H), 1.32(dd, J = 2.0, 4.4 Hz, 2H). 366.1 A 108 0.32

1H NMR (400 MHz, DMSO) δ 8.85 (s, 2H), 6.75 (s, 2H), 6.44 (s, 1H), 5.57(s, 1H), 4.78- 4.76 (m, 2H), 4.65 (s, 1H), 3.75 (dd, J = 7.3, 1.1 Hz,1H), 3.66 (d, J = 7.4 Hz, 1H), 3.47 (dd, J = 9.7, 1.3 Hz, 1H), 3.36 (s,2H), 3.12 (d, J = 9.8 Hz, 1H), 2.90 (dt, J = 6.2, 2.8 Hz, 1H), 1.93-1.82 (m, 4H), 1.33- 1.27 (m, 2H). 351 D 109 0.48

No NMR 368 C 110 0.02

¹H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 6.99 (s, 2H), 6.30- 6.10 (m,1H), 5.10- 4.90 (m, 1H), 4.83 (d, J = 6.8 Hz, 1H), 4.70- 4.64 (m, 1H),3.85- 3.76 (m, 1H), 3.66- 3.64 (m, 1H), 3.45- 3.38 (m, 4H), 2.91- 2.87(m, 1H), 1.93- 1.86 (m, 4H), 1.34- 1.29 (m, 2H). 352.1 A 111 0.15

1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.08 (s, 2H), 6.98 (s, 1H),4.29-4.21 (m, 1H), 3.96-3.91 (m, 2H), 3.63-3.48 (m, 2H), 3.43 (td, J =11.2, 3.4 Hz, 2H), 2.78-2.70 (m, 1H), 2.09-1.96 (m, 2H), 1.92-1.85 (m,1H), 1.82-1.73 (m, 4H), 1.71-1.64 (m, 1H), 1.25 (d, J = 6.2 Hz, 3H). 341C 112 0.06

1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.08 (s, 2H), 6.98 (s, 1H), 4.25(dd, J = 6.1, 4.2 Hz, 1H), 3.94 (dd, J = 9.7, 2.3 Hz, 2H), 3.64- 3.49(m, 2H), 3.43 (td, J = 11.3, 3.1 Hz, 2H), 2.79-2.69 (m, 1H), 2.10-1.95(m, 2H), 1.91-1.72 (m, 5H), 1.72-1.63 (m, 1H), 1.25 (d, J = 6.3 Hz, 3H).341 C 113 0.74

¹H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.36 (s, 1H), 6.96 (s,1H), 6.11 (s, 1H), 5.64 (s, 2H), 4.74- 4.67 (m, 4H), 4.38- 4.23 (m, 3H),3.93- 3.90 (m, 2H), 3.63- 3.56 (m, 1H), 3.35 (s, 3H), 2.98 (d, J = 10.8Hz, 2H), 2.54-2.46 (m, 1H), 2.06-1.99 (m, 2H), 1.93-1.88 (m, 4H). 464.0F 114 0.69

¹H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H), 8.36 (s, 1H), 6.89 (s,1H), 6.14 (s, 1H), 5.53 (s, 2H), 4.74- 4.69 (m, 5H), 4.38- 4.31 (m, 2H),4.20- 4.11 (m, 2H), 3.63- 3.60 (m, 1H), 3.00- 2.98 (m, 2H), 2.54- 2.49(m, 1H), 2.04- 1.90 (m, 6H). 452.0 F 115 0.49

¹H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.20 (s, 1H), 7.01 (s,1H), 6.24 (s, 1H). 5.66-5.34 (m, 1H), 4.72-4.71 (m, 2H), 4.66-4.62 (m,2H), 4.40-4.31 (m, 2H), 4.14-4.11 (m, 1H), 4.08-4.05 (m, 1H), 3.56-3.53(m, 1H), 2.94-2.92 (m, 2H), 2.61-2.52 (m, 1H), 2.03-2.00 (m, 2H),1.97-1.78 (m, 4H). 418.15 F 116 1.61

¹H NMR (400 MHz, Methanol-d4) δ 8.86 (s, 2H), 7.01 (s, 1H), 6.26 (s,1H), 5.53-5.36 (m, 1H), 4.74-4.71 (m, 2H), 4.65-4.62 (m, 2H). 4.40-4.31(m, 2H). 4.14-4.05 (m, 2H), 3.56-3.52 (m, 1H), 2.93 (d, J = 12.0 Hz,2H), 2.64-2.56 (m, 1H), 2.03-1.99 (m, 2H), 1.97-1.81 (m, 4H). 385.16 F117 0.71

1H NMR (400 MHz, DM SO) δ 8.93 (s, 2H), 7.00 (s, 2H), 6.60 (s, 1H),3.70-3.60 (m, 16H). 344 G 118 0.001

¹H NMR (400 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.01 (s, 1H), 6.71 (s,1H), 6.57 (t, J = 73.6 Hz, 1H), 4.97- 4.93 (m, 3H), 3.55 (s, 2H),3.50-3.47 (m, 2H), 3.38 (s, 3H), 3.22 (d, J = 8.4 Hz, 2H), 2.94- 2.92(m, 1H), 2.72- 2.69 (m, 2H), 2.52- 2.50 (m, 2H), 2.32 (s, 1H), 2.09 (s,2H), 1.98 (s, 2H), 1.46-1.44 (m, 2H). 459.15 C 119 0.002

¹H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.03 (s, 1H), 6.71 (s,1H), 6.58 (t, J = 73.2 Hz, 1H), 4.96 (s, 3H), 3.97 (d, J = 12.0 Hz, 1H),3.73 (s, 2H), 3.56 (s, 2H), 3.00-2.95 (m, 1H), 2.31 (s,2H), 2.07-2.00(m, 5H), 1.72 (s, 1H), 1.60 (d, J = 3.6 Hz, 1H), 1.47 (s, 2H). 443.15 C120 0.01

¹H NMR (400 MHz, Chloroform-d) δ 8.95 (s, 2H), 6.65 (s, 1H), 5.31 (s,2H), 4.97 (d, J = 7.2 Hz, 1H), 3.56 (s, 2H), 3.30 (d, J = 9.2 Hz, 2H),2.98-2.93 (m, 2H), 2.75 (d, J = 8.8 Hz, 2H), 2.50 (s, 2H), 2.10 (s, 1H),2.02 (s, 2H), 1.99 (s, 2H), 1.46-1.45 (m, 2H), 1.19 (s, 6H). 408.15 C121 0.003

¹H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.03 (s, 1H), 6.72 (s,1H), 6.58 (t, J = 73.2 Hz, 1H), 4.97- 4.93 (m, 3H), 4.71- 4.67 (m, 2H),4.69- 4.61 (m, 2H), 3.82- 3.79 (m, 1H), 3.56 (s, 2H), 3.14 (d, J = 8.8Hz, 2H), 2.95-2.93 (m, 1H), 2.50 (d, J = 8.4 Hz, 2H), 2.35-2.34 (m, 1H),2.13 (s, 2H), 1.99 (s, 2H), 1.49-1.45 (m, 2H). 457.12 C 122 0.02

¹H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.41 (s, 1H), 6.71 (s,1H), 4.98-4.92 (m, 1H), 4.69-4.62 (m, 2H), 4.62-4.59 (m, 2H), 3.82-3.75(m, 1H), 3.55 (s, 2H), 3.12 (d, J = 8.8 Hz, 2H), 2.93- 2.92 (m, 1H),2.49 (d, J = 8.4 Hz, 2H), 2.35- 2.33 (m, 1H), 2.12 (s, 2H), 2.00-1.98(m, 2H), 1.45-1.43 (m, 2H). 458.9 C 123 0.02

¹H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.15 (s, 1H), 7.10 (s, 1H),6.92 (s, 2H), 4.85-4.83 (m, 1H), 4.57-4.54 (m, 2H), 4.46-4.43 (m, 2H),3.72-3.69 (m, 1H), 3.45 (s, 2H), 3.06 (d, J = 8.8 Hz, 2H), 2.91-2.89 (m,1H), 2.40 (d, J = 8.4 Hz, 2H), 2.29 (s, 1H), 2.05 (s, 2H), 1.96 (s, 2H),1.33-1.32 (m, 2H). 474.9 C 124 0.02

¹H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.04 (s, 1H), 7.19 (s,1H), 6.58 (t, J = 73.2 Hz, 1H), 4.97 (s, 2H), 4.69-4.59 (m, 4H),3.81-3.75 (m, 1H), 3.12 (d, J = 8.8 Hz, 2H), 2.49 (d, J = 8.4 Hz, 2H),2.42-2.40 (m, 1H), 2.18-2.15 (m, 1H), 2.11 (s, 2H), 1.11- 1.08 (m, 2H),1.00- 0.97 (m, 2H). 416.1 C 125 0.11

¹H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 7.97 (s, 1H), 7.14 (s,1H), 6.52 (t, J = 73.6 Hz, 1H), 4.93 (s, 2H), 3.26-3.20 (m, 2H),3.05-3.00 (m, 2H), 2.71 (d, J = 8.8 Hz, 2H), 2.27-2.25 (m, 1H),2.11-2.10 (m, 1H), 2.04 (s, 2H), 1.18- 1.03 (m, 2H), 0.96- 0.91 (m, 2H).442.1 C 126 0.003

¹H NMR (400 MHz, Chloroform-d) δ 8.55 (s, 1H), 8.02 (s, 1H), 7.17 (s,1H), 6.58 (t, J = 73.2 Hz, 1H), 4.96 (s, 2H), 3.46 (t, J = 6.4 Hz, 2H),3.36 (s, 3H), 3.21 (d, J = 9.2 Hz, 2H), 2.70- 2.67 (m, 2H), 2.49 (d, J =8.8 Hz, 2H), 2.38 (s, 1H), 2.17-2.15 (m, 1H), 2.06 (s, 2H), 1.11- 1.18(m, 2H), 0.99- 0.96 (m, 2H). 418.2 C 127 0.001

¹H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.05 (s, 1H), 7.18 (s,1H), 6.60 (t, J = 73.2 Hz, 1H), 4.99 (s, 2H), 3.30 (d, J = 8.8 Hz, 2H),2.92-2.85 (m, 1H), 2.75 (d, J = 8.4 Hz, 2H), 2.51 (s, 2H), 2.34 (s, 1H),2.20-2.16 (m, 1H), 2.10 (s, 2H), 1.19 (s, 6H), 1.14-1.11 (m, 2H),1.10-1.00 (m, 2H). 432.2 C 128 0.008

¹H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.02 (s, 1H), 6.69 (s,1H), 6.58 (t, J = 73.6 Hz, 1H), 5.01- 4.94 (m, 3H), 3.98 (d, J = 8.4 Hz,1H), 3.75- 3.66 (m, 2H), 3.57- 3.55 (m, 3H), 2.95- 2.94 (m, 1H), 2.32-2.26 (m, 4H), 2.00 (s, 2H), 1.70-1.68 (m, 1H), 1.46-1.45 (m, 2H), 1.16(t, J = 7.6 Hz, 3H). 457.15 C 129 0.001

1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.99 (s, 1H), 7.17 (t, J =73.8 Hz, 1H), 6.43 (s, 2H), 5.51-5.30 (m, 1H), 4.99 (s, 1H),, 4.67 (s,1H), 3.93-3.74 (m, 3H), 3.74-3.44 (m, 4H), 3.35 (s, 1H), 2.28- 2.01 (m,2H), 1.92- 1.82 (m, 2H). 423 E 130 0.022

1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.98 (s, 1H), 7.16 (t, 1H),6.41 (s, 2H), 4.98 (s, 1H), 4.66 (s, 1H), 4.06-3.99 (m, 1H), 3.78 (d, J= 7.4 Hz, 1H), 3.70-3.53 (m, 4H), 3.46 (d, J = 10.1 Hz, 2H3.35 (s, 1H),3.26(s, 3H), 2.06-1.93 (m, 2H), 1.86 (s, 2H). 435 E 131 0.01

1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.94 (s, 1H), 7.15 (t, 1H),6.43 (s, 2H), 4.95 (s, 1H), 4.66 (s, 1H), 3.95 (s, 4H), 3.77 (d, J = 7.3Hz, 1H), 3.64 (d, J = 7.3 Hz, 1H), 3.43 (d, J = 10.4 Hz, 1H), 3.35 (s,1H), 2.15 (t, J = 7.6 Hz, 4H), 1.91-1.71 (m, 4H). 431 E 132 0.014

1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.97 (s, 1H), 7.16 (t, J =73.8 Hz, 1H), 6.42 (s, 2H), 4.98 (s, 1H), 4.66 (s, 1H), 4.50 (t, J = 5.6Hz, 1H), 3.85 (q, J = 7.4 Hz, 1H), 3.81- 3.68 (m, 4H), 3.65 (d, J = 7.3Hz, 1H), 3.59- 3.50 (m, 1H), 3.45 (d, J = 10.1 Hz, 1H), 3.35 (s, 1H),2.99-2.87 (m, 1H), 2.14-1.98 (m, 1H), 1.93-1.73 (m, 3H). 447 E 133 0.08

1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.94 (s, 1H), 7.37- 6.94 (m,1H), 6.45 (s, 2H), 4.97 (s, 1H), 4.67 (s, 1H), 3.97-3.89 (m, 2H),3.85-3.73 (m, 3H), 3.65 (d, J = 7.3 Hz, 1H), 3.44 (d, J = 10.4 Hz, 1H),3.40-3.30 (m, 1H), 3.20 (s, 3H), 1.86 (s, 2H), 1.44 (s, 3H). 435 E 1340.02

¹H NMR (400 MHz, DMSO) δ 8.53 (d, J = 1.9 Hz, 1H), 7.94 (s, 1H), 7.50(d, J = 1.9 Hz, 1H), 7.17 (t, J = 74.0 Hz, 1H), 7.16 (s, 1H), 6.35 (brs, 2H), 4.62- 4.50 (m, 2H), 4.45- 4.32 (m, 2H), 3.82- 3.70 (m, 1H),3.70- 3.60 (m, 3H), 3.28- 3.23 (m, 2H), 2.17- 2.03 (m, 1H), 1.05- 0.85(m, 4H) J

Example 3

DLK TR-FRET inhibition assay: DLK kinase reactions (20 μL) containing 5nM N-terminally GST-tagged DLK (catalytic domain amino acid 1-520)(Carna Bioscience), 40 nM N-terminally HIS-tagged MKK4 K131M substrate,and 30 μM ATP in kinase reaction buffer (50 mM HEPES, pH 7.5, 0.01%Triton X-100, 0.01% Bovine γ-Globulins, 2 mM DTT, 10 mM MgCl₂ and 1 mMEGTA), and testing compound 1:3 serial diluted starting at 20 uM wereincubated at ambient temperature for 60 minutes in 384 well OptiPlate(Perkin Elmer). To quench kinase reactions and detect phosphorylatedMKK4, 15 μL of TR-FRET antibody mixture containing 2 nManti-phosphorylated MKK4 labeled with Europium cryptate (Cisbio) and 23nM anti-HIS labeled with D2 (Cisbio) in detection buffer (25 mM Tris pH7.5, 100 mM NaCl, 100 mM EDTA, 0.01% Tween-20, and 200 mM KF) was addedto the reaction mixture. The detection mixture was incubated for 3 hoursat ambient temperature and the TR-FRET was detected with an EnVisionmultilabel plate reader (Perkin-Elmer) using the LANCE/DELFIA Dual Enhlabel from Perkin-Elmer (excitation filter: UV2 (TRF) 320 and emissionfilters: APC 665 and Europium 615). Compounds of formula I as set forthin Table 1 in Example 1 inhibited the DLK kinase with the Ks inmicromolar (μM).

1. Compounds of formula (I)

or salts thereof wherein R¹, R² and R³ are each independently H, F, Cl, Br, I, C₁₋₆ alkyl or C₁₋₆ haloalkyl; X¹ is N; X² is N or CH; A is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ dialkylamino, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, wherein A is optionally substituted with 1-5 R^(A) substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO₂, —SF₅, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ heteroalkyl, -(L^(A))₀₋₁-3-8 membered cycloalkyl, -(L^(A))₀₋₁-3-8 membered heterocycloalkyl, -(L^(A))₀₋₁-5 to 6 membered heteroaryl, -(L^(A))₀₋₁-C₆ aryl, -(L^(A))₀₋₁-NR^(R1a)R^(R1b), -(L^(A))₀₋₁-OR^(R1a), -(L^(A))₀₋₁-SR^(R1a), -(L^(A))₀₋₁-N(R^(R1a))C(═Y¹)OR^(R1c), -(L^(A))₀₋₁-OC(═O)N(R^(R1a))(R^(R1b)), -(L^(A))₀₋₁-N(R^(R1a))C(═O)N(R^(R1a))(R^(R1b)), -(L^(A))₀₋₁-C(═O)N(R^(R1a))(R^(R1b)), -(L^(A))₀₋₁-N(R^(R1a))C(═O)R^(R1b), -(L^(A))₀₋₁-C(═O)OR^(R1a), -(L^(A))₀₋₁-OC(═O)R^(R1a), -(L^(A))₀₋₁-P(═O)(OR^(R1a))(OR^(R1b)), -(L^(A))₀₋₁-S(O)₁₋₂R^(R1c), -(L^(A))₀₋₁—S(O)₁₋₂N(R_(R1a))(R^(R1b)), -(L^(A))₀₋₁-N(R^(R1a))S(O)₁₋₂N(R^(R1a))(R^(R1b)) and -(L^(A))₀₋₁-N(R^(R1a))S(O)₁₋₂(R^(R1c)), wherein L^(A) is selected from the group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₁₋₄ alkoxylene, C₁₋₄ aminoalkylene, C₁₋₄ thioalkylene, C₂₋₄ alkenylene, and C₂₋₄ alkynylene; wherein R^(R1a) and R^(R1b) are independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R^(R1c) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, 3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7 membered heterocycloalkyl, and wherein R^(A) is optionally substituted on carbon atoms and heteroatoms with R^(RA) substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, —SF₅, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄(halo)alkyl-C(═O)—, C₁₋₄(halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-N(H)S(O)₀₋₂—, C₁₋₄(halo)alkyl-S(O)₀₋₂N(H)—, (halo)alkyl-N(H)—S(O)₀₋₂N(H)—, C₁₋₄ (halo)alkyl-C(═O)N(H)—, C₁₋₄(halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylthio, C₁₋₄ alkylamino and C₁₋₄ dialkylamino; and Cy is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, wherein Cy is optionally substituted on carbon or heteroatoms with R^(Cy) substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO₂, —SF₅, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ heteroalkyl, -(L^(Cy))₀₋₁-3-8 membered cycloalkyl, -(L^(Cy))₀₋₁-3-8 membered heterocycloalkyl, -(L^(Cy))₀₋₁-5 to 6 membered heteroaryl, -(L^(Cy))₀₋₁-phenyl, -(L^(Cy))₀₋₁-NR^(RCa)R^(RCb), -(L^(Cy))₀₋₁-OR^(RCa), -(L^(Cy))₀₋₁-SR^(RCa), -(L^(Cy))₀₋₁-N(R^(RCa))C(═Y¹)OR^(RCc), -(L^(Cy))₀₋₁-OC(═O)N(R^(RCa))(R^(RCb)), -(L^(Cy))₀₋₁-N(R^(RCa))C(═O)N(R^(RCa))(R^(RCb)), -(L^(Cy))₀₋₁-C(═O)N(R^(RCa))(R^(RCb)), -(L^(Cy))₀₋₁-N(R^(RCa))C(═O)R^(RCb), -(L^(Cy))₀₋₁-C(═O)OR^(RCa), -(L^(Cy))₀₋₁-OC(═O)R^(RCa), -(L^(Cy))₀₋₁-P(═O)(OR^(RCa))(OR^(RCb)), -(L^(Cy))₀₋₁-S(O)₁₋₂R^(RCc), -(L^(Cy))₀₋₁-S(O)₁₋₂N(R^(RCa))(R^(RCb)), (L^(Cy))₀₋₁-N(R^(RCa))S(O)₁₋₂N(R^(RCa))(R^(RCb)) and -(L^(C)Y)₀₋₁—N(R^(RCa))S(O)₁₋₂(R^(RCc)), wherein L^(Cy) is selected from the group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₁₋₄ alkoxylene, C₁₋₄ aminoalkylene, C₁₋₄ thioalkylene, C₂₋₄ alkenylene, and C₂₋₄ alkynylene; wherein R^(RCa) and R^(RCb) are independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R^(RCc) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, 3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7 membered heterocycloalkyl, and wherein R^(Cy) is optionally substituted on carbon atoms and heteroatoms with from 1 to 5 R^(RCy) substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, —SF₅, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄(halo)alkyl-C(═O)—, C₁₋₄ (halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-N(H)S(O)₀₋₂—, C₁₋₄ (halo)alkyl-S(O)₀₋₂N(H)—, (halo)alkyl-N(H)—S(O)₀₋₂N(H)—, C₁₋₄ (halo)alkyl-C(═O)N(H)—, C₁₋₄ (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylthio, C₁₋₄ alkylamino and C₁₋₄ dialkylamino. 2-4. (canceled)
 5. A compound of claim 1, wherein X² is N.
 6. A compound of claim 1, wherein X² is C(H). 7-12. (canceled)
 13. A compound of claim 1, wherein R¹, R² and R³ are each independently selected from the group consisting of F, Cl, CN, hydrogen, C₁₋₄ alkyl and C₁₋₄ haloalkyl.
 14. A compound of claim 1, wherein R¹, R² and R³ are each hydrogen.
 15. A compound of claim 1, wherein A and Cy are independently selected from the group consisting of pyrrolidine, piperidine, azetidine, azepane, piperazine, 7-azaspiro[3.5]nonane, 3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, morpholine, hexahydro-2H-furo[3,2-c]pyrrole, 2-azabicyclo[2.1.1]hexane, 2,5-diazabicyclo[2.2.1]heptane, 2-aza-tricyclo[3.3.1.1-3,7]decane, 2-azabicyclo[2.1.1]hexane, 9-azabicyclo[4.2.1]nonane, 9-azabicyclo[3.3.1]nonane, cyclobutane, cyclopropane, cyclopentane, 2-thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide, 2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran, 8-azabicyclo[3.2.1]octane and 3-oxa-8-azabicyclo[3.2.1]octane, and is optionally substituted.
 16. A compound of claim 1, wherein A is selected from the group consisting of pyrrolidine, piperidine, azetidine, azepane, piperazine, cyclopropane, cyclobutane, cyclopentane, 7-azaspiro[3.5]nonane, 3-oxabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, morpholine, hexahydro-2H-furo[3,2-c]pyrrole and 2-azabicyclo[2.1.1]hexane, and is optionally substituted.
 17. (canceled)
 18. A compound of claim 1, wherein A is selected from the group consisting of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,5 S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, (1R,5 S)-3-oxabicyclo[3.1.0]hexane, (1S,5R)-3-oxabicyclo[3.1.0]hexane, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane and (1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally substituted.
 19. A compound of claim 1, wherein is A is selected from the group consisting of methyl, ethyl, isopropyl,


20. A compound of claim 1, wherein Cy is selected from the group consisting of 2,5-diazabicyclo[2.2.1]heptane, piperidine, pyrrolidine, azetidine, 2-aza-tricyclo[3.3.1.1-3,7]decane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, 2-azabicyclo[2.1.1]hexane, 9-azabicyclo[4.2.1]nonane, 9-azabicyclo[3.3.1]nonane, cyclobutane, 2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide, 2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran, 8-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, and is optionally substituted.
 21. A compound of claim 1, wherein Cy is selected from the group consisting of azetidine, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,5S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, (1R,5S)-3-oxabicyclo[3.1.0]hexane, (1S,5R)-3-oxabicyclo[3.1.0]hexane, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane and (1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally substituted.
 22. A compound of claim 1, wherein Cy is selected from the group consisting of

23-27. (canceled)
 28. A compound of claim of claim 1, wherein Cy is optionally substituted with 1 to 5 R^(Cy) substituents selected from the group consisting of F, Cl, Br, I, CN, OH, 2,3-difluorophen-1-yl-C(═O)—, 4-fluorophen-1-yl-C(═O)—, 3-fluorophen-1-yl-C(═O)—, 3,5-difluorophen-1-yl-C(═O)—, 3-fluoro-4-methyl-phen-1-yl-C(═O)—, 2,5-difluorophen-1-yl-C(═O)—, oxetane, oxetan-3-yl, thiazole, thiazol-2-yl, —CH₃CH₂C(═O)—, CH₃C(═O)—, CF₃CH₂—, (HO)C(CH₃)₂CH₂—, CH₃OCH₂CH₂—, CH₃OC(CH₃)₂C(═O)—, CH₃OCH₂C(═O)—, isopropyl, ethyl and methyl.
 29. A compound of claim 1, wherein A is optionally substituted with 1 to 5 R^(A) substituents selected from the group consisting of F, Cl, Br, I, CN, CH₃O—, CH₃, cyclopropylmethyl, CF₃ and butyl.
 30. A compound of claim 1, wherein said compound is selected from the subformula consisting of


31. (canceled)
 32. A compound of claim 1, wherein said compound is selected from the subformula consisting of

wherein R^(Cy) if present replaces a hydrogen atom attached to a carbon or nitrogen atom of the Cy ring.
 33. (canceled)
 34. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, diluent or excipient. 35-46. (canceled)
 47. A method for decreasing the progression of a neurodegenerative disease or condition in a patient suffering therefrom comprising administering to said patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. 4-49. (canceled)
 50. The method of claim 47, wherein the compound of formula I is administered in combination with one or more additional pharmaceutical agents.
 51. The compound of claim 1, or a pharmaceutically acceptable salt thereof, said compound selected from the group consisting of:


52. A method of preparing a compound of claim
 1. 